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1
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Stefania K, Ashok KK, Geena PV, Katarina P, Isak D. TMAO enhances TNF-α mediated fibrosis and release of inflammatory mediators from renal fibroblasts. Sci Rep 2024; 14:9070. [PMID: 38643262 PMCID: PMC11032383 DOI: 10.1038/s41598-024-58084-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/25/2024] [Indexed: 04/22/2024] Open
Abstract
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite and TNF-α is proinflammatory cytokine, both known to be associated with renal inflammation, fibrosis and chronic kidney disease. However, today there are no data showing the combined effect of TMAO and TNF-α on renal fibrosis-and inflammation. The aim of this study was to investigate whether TMAO can enhance the inflammatory and fibrotic effects of TNF-α on renal fibroblasts. We found that the combination of TNF-α and TMAO synergistically increased fibronectin release and total collagen production from renal fibroblasts. The combination of TMAO and TNF-α also promoted increased cell proliferation. Both renal proliferation and collagen production were mediated through Akt/mTOR/ERK signaling. We also found that TMAO enhanced TNF-α mediated renal inflammation by inducing the release of several cytokines (IL-6, LAP TGF-beta-1), chemokines (CXCL-6, MCP-3), inflammatory-and growth mediators (VEGFA, CD40, HGF) from renal fibroblasts. In conclusion, we showed that TMAO can enhance TNF-α mediated renal fibrosis and release of inflammatory mediators from renal fibroblasts in vitro. Our results can promote further research evaluating the combined effect of TMAO and inflammatory mediators on the development of kidney disease.
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Affiliation(s)
- Kapetanaki Stefania
- School of Medical Sciences, Örebro University, Campus USÖ, 701 82, Örebro, Sweden.
- Nephrology Department, Karolinska University Hospital, 171 76, Solna, Sweden.
- Nephrology Department, Karolinska University Hospital, 141 86, Huddinge, Stockholm, Sweden.
| | - Kumawat Kumar Ashok
- School of Medical Sciences, Örebro University, Campus USÖ, 701 82, Örebro, Sweden
| | | | - Persson Katarina
- School of Medical Sciences, Örebro University, Campus USÖ, 701 82, Örebro, Sweden
| | - Demirel Isak
- School of Medical Sciences, Örebro University, Campus USÖ, 701 82, Örebro, Sweden
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2
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Tsokos GC, Boulougoura A, Kasinath V, Endo Y, Abdi R, Li H. The immunoregulatory roles of non-haematopoietic cells in the kidney. Nat Rev Nephrol 2024; 20:206-217. [PMID: 37985868 PMCID: PMC11005998 DOI: 10.1038/s41581-023-00786-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2023] [Indexed: 11/22/2023]
Abstract
The deposition of immune complexes, activation of complement and infiltration of the kidney by cells of the adaptive and innate immune systems have long been considered responsible for the induction of kidney damage in autoimmune, alloimmune and other inflammatory kidney diseases. However, emerging findings have highlighted the contribution of resident immune cells and of immune molecules expressed by kidney-resident parenchymal cells to disease processes. Several types of kidney parenchymal cells seem to express a variety of immune molecules with a distinct topographic distribution, which may reflect the exposure of these cells to different pathogenic threats or microenvironments. A growing body of literature suggests that these cells can stimulate the infiltration of immune cells that provide protection against infections or contribute to inflammation - a process that is also regulated by draining kidney lymph nodes. Moreover, components of the immune system, such as autoantibodies, cytokines and immune cells, can influence the metabolic profile of kidney parenchymal cells in the kidney, highlighting the importance of crosstalk in pathogenic processes. The development of targeted nanomedicine approaches that modulate the immune response or control inflammation and damage directly within the kidney has the potential to eliminate the need for systemically acting drugs.
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Affiliation(s)
- George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | | | - Vivek Kasinath
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yushiro Endo
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Reza Abdi
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hao Li
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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3
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Yang T, Li L, Heng C, Sha P, Wang Y, Shen J, Jiang Z, Qian S, Wei C, Yang H, Zhu X, Wang T, Wu M, Wang J, Lu Q, Yin X. Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating the tight junctions of renal tubular epithelial cells. Food Funct 2024; 15:2628-2644. [PMID: 38358014 DOI: 10.1039/d2fo00940d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
As one of the most significant pathological changes of diabetic nephropathy (DN), tubulointerstitial fibrosis (TIF) had a close relationship with tubulointerstitial inflammation (TI), and the occurrence of TI could have resulted from the disrupted tight junctions (TJs) of renal tubular epithelial cells (RTECs). Studies have demonstrated that sodium butyrate (NaB), a typical short chain fatty acid (SCFA), played an important regulatory role in intestinal TJs and inflammation. In this study, our in vivo and in vitro results showed that accompanied by TI, renal tubular TJs were gradually disrupted in the process of DN-related TIF. In HG and LPS co-cultured HK-2 cells and db/db mice, NaB treatment regained the TJs of RTECs via the sphingosine 1-phosphate receptor-1 (S1PR1)/AMPK signaling pathway, relieving inflammation. Small interfering RNA of S1PR1, S1PR1 antagonist W146 and agonist SEW2871, and AMPK agonist AICAR were all used to further confirm the essential role of the S1PR1/AMPK signaling pathway in NaB's TJ protection in RTECs in vitro. Finally, NaB administration not only improved the renal function and TIF, but also relieved the TI of db/db mice. These findings suggested that the use of NaB might be a potential adjuvant treatment strategy for DN-associated TIF, and this protective effect was linked to the TJ modulation of RTECs via the S1PR1/AMPK signaling pathway, leading to the improvement of TI.
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Affiliation(s)
- Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Lin Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Cai Heng
- Department of Pharmacy, JingJiang People's Hospital, Jingjiang 214500, China
| | - Pian Sha
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Yiying Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Jiaming Shen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Zhenzhou Jiang
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Sitong Qian
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Chujing Wei
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Hao Yang
- Department of Pharmacy, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou 213000, China
| | - Xia Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Tao Wang
- Department of Pharmacy, The affiliated hospital of Xuzhou Medical University, Xuzhou 221006, China
| | - Mengying Wu
- New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Jianyun Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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4
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Fountoglou A, Deltas C, Siomou E, Dounousi E. Genome-wide association studies reconstructing chronic kidney disease. Nephrol Dial Transplant 2024; 39:395-402. [PMID: 38124660 PMCID: PMC10899781 DOI: 10.1093/ndt/gfad209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Indexed: 12/23/2023] Open
Abstract
Chronic kidney disease (CKD) is a major health problem with an increasing epidemiological burden, and is the 16th leading cause of years of life lost worldwide. It is estimated that more than 10% of the population have a variable stage of CKD, while about 850 million people worldwide are affected. Nevertheless, public awareness remains low, clinical access is inappropriate in many circumstances and medication is still ineffective due to the lack of clear therapeutic targets. One of the main issues that drives these problems is the fact that CKD remains a clinical entity with significant causal ambiguity. Beyond diabetes mellitus and hypertension, which are the two major causes of kidney disease, there are still many gray areas in the diagnostic context of CKD. Genetics nowadays emerges as a promising field in nephrology. The role of genetic factors in CKD's causes and predisposition is well documented and thousands of genetic variants are well established to contribute to the high burden of disease. Next-generation sequencing is increasingly revealing old and new rare variants that cause Mendelian forms of chronic nephropathy while genome-wide association studies (GWAS) uncover common variants associated with CKD-defining traits in the general population. In this article we review how GWAS has revolutionized-and continues to revolutionize-the old concept of CKD. Furthermore, we present how the investigation of common genetic variants with previously unknown kidney significance has begun to expand our knowledge on disease understanding, providing valuable insights into disease mechanisms and perhaps paving the way for novel therapeutic targets.
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Affiliation(s)
- Anastasios Fountoglou
- Department of Nephrology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Constantinos Deltas
- School of Medicine and biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus
| | - Ekaterini Siomou
- Department of Pediatrics, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Evangelia Dounousi
- Department of Nephrology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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Zhang XJ, Liu CC, Li ZL, Ding L, Zhou Y, Zhang DJ, Zhang Y, Hou ST, Ma RX. Sacubitril/valsartan ameliorates tubulointerstitial fibrosis by restoring mitochondrial homeostasis in diabetic kidney disease. Diabetol Metab Syndr 2024; 16:40. [PMID: 38341600 DOI: 10.1186/s13098-024-01284-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Tubulointerstitial fibrosis plays an important role in the progression of diabetic kidney disease (DKD). Sacubitril/valsartan (Sac/Val) exerts a robust beneficial effect in DKD. However, the potential functional effect of Sac/Val on tubulointerstitial fibrosis in DKD is still largely unclear. METHODS Streptozotocin-induced diabetic mice were given Sac/Val or Val by intragastric administration once a day for 12 weeks. The renal function, the pathological changes of tubule injury and tubulointerstitial fibrosis, as well as mitochondrial morphology of renal tubules in mice, were evaluated. Genome-wide gene expression analysis was performed to identify the potential mechanisms. Meanwhile, human tubular epithelial cells (HK-2) were cultured in high glucose condition containing LBQ657/valsartan (LBQ/Val). Further, mitochondrial functions and Sirt1/PGC1α pathway of tubular epithelial cells were assessed by Western blot, Real-time-PCR, JC-1, MitoSOX or MitoTracker. Finally, the Sirt1 specific inhibitor, EX527, was used to explore the potential effects of Sirt1 signaling in vivo and in vitro. RESULTS We found that Sac/Val significantly ameliorated the decline of renal function and tubulointerstitial fibrosis in DKD mice. The enrichment analysis of gene expression indicated metabolism as an important modulator in DKD mice with Sac/Val administration, in which mitochondrial homeostasis plays a pivotal role. Then, the decreased expression of Tfam and Cox IV;, as well as changes of mitochondrial function and morphology, demonstrated the disruption of mitochondrial homeostasis under DKD conditions. Interestingly, Sac/Val administration was found to restore mitochondrial homeostasis in DKD mice and in vitro model of HK-2 cells. Further, we demonstrated that Sirt1/PGC1α, a crucial pathway in mitochondrial homeostasis, was activated by Sac/Val both in vivo and in vitro. Finally, the beneficial effects of Sac/Val on mitochondrial homeostasis and tubulointerstitial fibrosis was partially abolished in the presence of Sirt1 specific inhibitor. CONCLUSIONS Taken together, we demonstrate that Sac/Val ameliorates tubulointerstitial fibrosis by restoring Sirt1/PGC1α pathway-mediated mitochondrial homeostasis in DKD, providing a theoretical basis for delaying the progression of DKD in clinical practice.
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Affiliation(s)
- Xing-Jian Zhang
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Cong-Cong Liu
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zuo-Lin Li
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
| | - Lin Ding
- Department of Nephrology, Minda Hospital Affiliated to Hubei Minzu University, Enshi, Hubei, China
| | - Yan Zhou
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Dong-Jie Zhang
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yao Zhang
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shu-Ting Hou
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Rui-Xia Ma
- Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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Guo C, Cui Y, Jiao M, Yao J, Zhao J, Tian Y, Dong J, Liao L. Crosstalk between proximal tubular epithelial cells and other interstitial cells in tubulointerstitial fibrosis after renal injury. Front Endocrinol (Lausanne) 2024; 14:1256375. [PMID: 38260142 PMCID: PMC10801024 DOI: 10.3389/fendo.2023.1256375] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 11/22/2023] [Indexed: 01/24/2024] Open
Abstract
The energy needs of tubular epithelial components, especially proximal tubular epithelial cells (PTECs), are high and they heavily depend on aerobic metabolism. As a result, they are particularly vulnerable to various injuries caused by factors such as ischemia, proteinuria, toxins, and elevated glucose levels. Initial metabolic and phenotypic changes in PTECs after injury are likely an attempt at survival and repair. Nevertheless, in cases of recurrent or prolonged injury, PTECs have the potential to undergo a transition to a secretory state, leading to the generation and discharge of diverse bioactive substances, including transforming growth factor-β, Wnt ligands, hepatocyte growth factor, interleukin (IL)-1β, lactic acid, exosomes, and extracellular vesicles. By promoting fibroblast activation, macrophage recruitment, and endothelial cell loss, these bioactive compounds stimulate communication between epithelial cells and other interstitial cells, ultimately worsening renal damage. This review provides a summary of the latest findings on bioactive compounds that facilitate the communication between these cellular categories, ultimately leading to the advancement of tubulointerstitial fibrosis (TIF).
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Affiliation(s)
- Congcong Guo
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yuying Cui
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- First Clinical Medical College, Shandong University of Traditional Chinese Medicin, Jinan, Shandong, China
| | - Mingwen Jiao
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Jinming Yao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Junyu Zhao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Yutian Tian
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- Shandong Institute of Nephrology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
- First Clinical Medical College, Shandong University of Traditional Chinese Medicin, Jinan, Shandong, China
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Xue R, Xiao H, Kumar V, Lan X, Malhotra A, Singhal PC, Chen J. The Molecular Mechanism of Renal Tubulointerstitial Inflammation Promoting Diabetic Nephropathy. Int J Nephrol Renovasc Dis 2023; 16:241-252. [PMID: 38075191 PMCID: PMC10710217 DOI: 10.2147/ijnrd.s436791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/30/2023] [Indexed: 02/12/2024] Open
Abstract
Diabetic nephropathy (DN) is a common complication affecting many diabetic patients, leading to end-stage renal disease. However, its pathogenesis still needs to be fully understood to enhance the effectiveness of treatment methods. Traditional theories are predominantly centered on glomerular injuries and need more explicit explanations of recent clinical observations suggesting that renal tubules equally contribute to renal function and that tubular lesions are early features of DN, even occurring before glomerular lesions. Although the conventional view is that DN is not an inflammatory disease, recent studies indicate that systemic and local inflammation, including tubulointerstitial inflammation, contributes to the development of DN. In patients with DN, intrinsic tubulointerstitial cells produce many proinflammatory factors, leading to medullary inflammatory cell infiltration and activation of inflammatory cells in the interstitial region. Therefore, understanding the molecular mechanism of renal tubulointerstitial inflammation contributing to DN injury is of great significance and will help further identify key factors regulating renal tubulointerstitial inflammation in the high glucose environment. This will aid in developing new targets for DN diagnosis and treatment and expanding new DN treatment methods.
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Affiliation(s)
- Rui Xue
- Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China
| | - Haiting Xiao
- Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Vinod Kumar
- Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Xiqian Lan
- Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Ashwani Malhotra
- Feinstein Institute for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA
| | - Pravin C Singhal
- Feinstein Institute for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA
| | - Jianning Chen
- Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China
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Liu W, Zhou H, Dong H, Xing D, Lu M. Fluorofenidone Attenuates Renal Interstitial Fibrosis by Enhancing Autophagy and Retaining Mitochondrial Function. Cell Biochem Biophys 2023; 81:777-785. [PMID: 37735328 DOI: 10.1007/s12013-023-01176-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND Fluorofenidone (AKF-PD) is a novel pyridone agent and has potent anti-NLRP3 inflammasome and anti-fibrotic activities. However, the mechanisms underlying its pharmacological actions are not fully understood. METHODS A renal fibrosis rat model was established by the unilateral ureteral obstruction (UUO) procedure and the rats were randomized and treated with, or without, AKF-PD for 3 and 7 days. The levels of renal fibrosis, NLRP3 inflammasome activation, mitochondrial function, and autophagy were tested in rat kidney tissues. Macrophages following lipopolysaccharides (LPS) and adenosine 5'-triphosphate (ATP) stimulation were examined by Western blot, spectrophotometry, and TEM. RESULTS Compared with the untreated UUO rats, AKF-PD treatment significantly mitigated the UUO procedure-induced renal fibrosis in rats. AKF-PD treatment decreased mitochondrial dysfunction and IL-Iβ and caspase-1 expression in rat kidney tissues and reduced mitochondrial reactive oxygen species production in activated macrophages. Mechanistically, AKF-PD treatment significantly attenuated the PI3K/AKT/mTOR signaling, increased Beclin-1 and LC3 II expression and autophagosome formation, and ameliorated the mitochondrial damage in renal tissues and activated macrophages. CONCLUSION The results indicated that AKF-PD treatment inhibited renal interstitial fibrosis by regulating the autophagy-mitochondria-NLRP3 inflammasome pathway.
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Affiliation(s)
- Wenlin Liu
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Hongli Zhou
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Haonan Dong
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Di Xing
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Miaomiao Lu
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121001, China.
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9
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Keneni M, Murugan R, Bizuwork K, Asfaw T, Tekle S, Tolosa G, Desalew A. Risk factors associated with acute kidney injury in a pediatric intensive care unit in Addis Ababa Ethiopia: case-control study. BMC Nephrol 2023; 24:279. [PMID: 37735373 PMCID: PMC10514953 DOI: 10.1186/s12882-023-03322-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 09/05/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a serious health problem in critically ill children. It is associated with poor treatment outcomes and high morbidity and mortality rates. Globally, one in three critically ill children suffers from acute kidney injury. However, limited data are available in Africa, particularly Ethiopia, which highlighting the risk factors related to acute kidney injury. Therefore, this study aimed to identify the risk factors associated with acute kidney injury among critically ill children admitted to the pediatric intensive care unit (PICU) at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. METHODS A facility-based unmatched case-control study was carried out on 253 (85 cases and 168 controls) critically ill children admitted to the pediatric intensive care unit from January 2011 to December 2021. Participants were selected using a systematic random sampling technique for the control group and all cases consecutively. Data were collected using a structured checklist. Data were entered using Epi data version 4.6 and analyzed using SPSS version 25. Multivariable analysis was carried out using the adjusted odds ratio (aOR) with a 95% confidence interval (CI) to identify associated factors with acute kidney injury. Statistical significance was set at P < 0.05. RESULTS The median age of the participants was two years. Approximately 55.6% of cases and 53.1% of controls were females. The diagnosis of hypertension (aOR = 5.36; 95% CI: 2.06-13.93), shock (aOR = 3.88, 95% CI: 1.85-8.12), exposure to nephrotoxic drugs (aOR = 4.09; 95% CI: 1. 45- 11.59), sepsis or infection aOR = 3.36; 95% CI: 1.42-7.99), nephritic syndrome (aOR = 2.97; 95% CI:1.19, 7.43), and use of mechanical ventilation aOR = 2.25, 95% CI: 1.12, 4.51) were significantly associated factors with acute kidney injury. CONCLUSION The diagnosis of sepsis or infection, hypertension, shock, nephrotoxic drugs, demand for mechanical ventilation support, and nephritic syndrome increased the risk of AKI among critically ill children. Multiple risk factors for AKI are associated with illness and severity. All measures that ensure adequate renal perfusion must be taken in critically ill children with identified risk factors to prevent the development of AKI.
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Affiliation(s)
- Mulualem Keneni
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Rajalakshmi Murugan
- School of Nursing and Midwifery, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
| | - Ketema Bizuwork
- School of Nursing and Midwifery, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tesfaye Asfaw
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Sosina Tekle
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Gadissa Tolosa
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Assefa Desalew
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia.
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10
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Sharma V, Singh TG. Drug induced nephrotoxicity- A mechanistic approach. Mol Biol Rep 2023; 50:6975-6986. [PMID: 37378746 DOI: 10.1007/s11033-023-08573-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023]
Abstract
The main goal of the treatment of patients is its effectiveness and safety. However, all currently prescribed drugs being used also have certain adverse effects, which might be seen as an unavoidable but necessary cost of pharmacotherapy. The kidney is the primary organ for xenobiotics elimination, making it particularly susceptible to the harmful effects of drugs and their metabolites during their excretion from the body. Moreover, certain medications have a preferential nephrotoxicity potential, which means that using them increases the risk of kidney injury. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, there is presently no accepted definition of drug-induced nephrotoxicity and no established diagnostic criteria. The current review briefly describes the pathogenic mechanism of drug-induced nephrotoxicity, the various basic drugs with nephrotoxicity potential and the renal biomarkers for the treatment of the drug-related kidney damage.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India, 140401
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India, 140401.
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11
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Zhang L, Wang X, He S, Zhang F, Li Y. Gypenosides suppress fibrosis of the renal NRK-49F cells by targeting miR-378a-5p through the PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116466. [PMID: 37031821 DOI: 10.1016/j.jep.2023.116466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/20/2023] [Accepted: 04/03/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The incidence of renal fibrosis caused by chronic kidney disease is increasing year by year. Preventing the activation and conversion of kidney-intrinsic fibroblasts to a myofibroblast phenotype is an important target for blocking the development of renal interstitial fibrosis. Our team established a stable renal interstitial fibrosis cell model in the early stage, and the screening results showed that GPs has good anti-fibrosis potential. At this stage, only a few literatures have reported its anti-fibrosis effect, and the mechanism of action is still unclear. AIM OF THE STUDY The massive synthesis and secretion of extracellular-matrix (ECM) components by activated fibroblasts in the kidneys causes irreversible renal interstitial fibrosis. Gypenosides (GPs) have been shown to decelerate this process, in which micro RNAs (miRNAs) play an important regulatory role. This study aimed to evaluate the mechanism underlying the suppressive effect of GPs on renal fibrosis. MATERIALS AND METHODS This study used TGF-β1-stimulated NRK-49F renal cells as an in-vitro model of renal interstitial fibrosis. First, the concentration range of GPs that significantly affects the cytoactive was determined. Then, the anti-fibrotic effects of various concentrations of GPs in the in-vitro model were assessed via immunofluorescence, western blotting, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Non-coding-RNA sequencing combined with bioinformatics was used to predict the mechanistic basis of the anti-fibrotic effect of GPs, and qRT-PCR was used to verify the sequencing results and bioinformatic predictions. The identified relationships of the anti-fibrotic effect of GPs with miR-378a-5p and the PI3K/AKT signaling were evaluated using a miR-NC mimic and the PI3K inhibitor LY294002 as controls, respectively. RESULTS TGF-β1 stimulation up-regulated α-SMA, COL1, and COL3 in NRK-49F cells, and this effect was suppressed by GPs. Additionally, TGF-β1 stimulation significantly changed the expression levels of 151 miRNAs, and GPs significantly suppressed the effect of TGF-β1 on the levels of 18 of these miRNAs. Among them, miR-3588 and miR-378a-5p were down-regulated, and miR-135b-5p and miR-3068-5p were up-regulated upon TGF-β1 induction. Of these miRNAs, miR-378a-5p was predicted to target the mRNAs of numerous proteins mainly enriched in the PI3K/AKT signaling pathway. The miRNA transfection experiments with the miR-NC mimic and PI3K inhibitor as controls showed that miR-378a-5p overexpression could suppress the TGF-β1-induced up-regulation of α-SMA, COL1, PI3K, and AKT, including the phosphorylated form (p-AKT). CONCLUSION GPs inhibit the PI3K/AKT signaling by up-regulating miR-378a-5p in TGF-β1-stimulated NRK-49F cells and thereby reduce their massive secretion of ECM components. Given that this in-vitro model of renal interstitial fibrosis closely mimics the in-vivo pathogenesis, our results most likely apply to the in-vivo conditions.
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Affiliation(s)
- Lan Zhang
- Chinese Medicine School, Beijing University of Chinese Medicine, No.11 East Road, North 3rd Ring Road, Beijing, 100029, China.
| | - Xiting Wang
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55 Zhongguancun East Road, Beijing, 100190, China.
| | - Shuangshuang He
- Chinese Medicine School, Beijing University of Chinese Medicine, No.11 East Road, North 3rd Ring Road, Beijing, 100029, China.
| | - Fang Zhang
- Chinese Medicine School, Beijing University of Chinese Medicine, No.11 East Road, North 3rd Ring Road, Beijing, 100029, China.
| | - Yu Li
- Chinese Medicine School, Beijing University of Chinese Medicine, No.11 East Road, North 3rd Ring Road, Beijing, 100029, China.
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12
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Iizuka K, Yabe D, Abu-Farha M, Abubaker J, Al-Mulla F. Editorial: Advances in the research of diabetic nephropathy, volume II. Front Endocrinol (Lausanne) 2023; 14:1135265. [PMID: 36742377 PMCID: PMC9890146 DOI: 10.3389/fendo.2023.1135265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 01/09/2023] [Indexed: 01/19/2023] Open
Affiliation(s)
- Katsumi Iizuka
- Department of Clinical Nutrition, Fujita Health University, Toyoake, Japan
- *Correspondence: Katsumi Iizuka,
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Center for One Medicine Innovative Research, Gifu University Institute for Advanced Study, Gifu, Japan
- Center for Healthcare Information Technology, Tokai National Higher Education and Research System, Nagoya, Japan
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman, Kuwait
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13
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TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling. Int J Mol Sci 2022; 23:ijms23168856. [PMID: 36012119 PMCID: PMC9407713 DOI: 10.3390/ijms23168856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 11/23/2022] Open
Abstract
Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counteracted the suppressive effect of TMAO on megalin expression. Our results may further help us unravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
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14
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Zheng Y, Yue X, Fang C, Jia Z, Chen Y, Xie H, Zhao J, Yang Z, Li L, Chen Z, Bian E, Zhao B. A Novel Defined Endoplasmic Reticulum Stress-Related lncRNA Signature for Prognosis Prediction and Immune Therapy in Glioma. Front Oncol 2022; 12:930923. [PMID: 35847925 PMCID: PMC9282894 DOI: 10.3389/fonc.2022.930923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are a group of the most aggressive primary central nervous system tumors with limited treatment options. The abnormal expression of long non-coding RNA (lncRNA) is related to the prognosis of glioma. However, the role of endoplasmic reticulum (ER) stress-associated lncRNAs in glioma prognosis has not been reported. In this paper, we obtained ER stress-related lncRNAs by co-expression analysis, and then a risk signature composed of 6 ER stress-related lncRNAs was constructed using Cox regression analysis. Glioma samples in The Cancer Genome Atlas (TCGA) were separated into high- and low-risk groups based on the median risk score. Compared with the low-risk group, patients in the high-risk group had shorter survival times. Additionally, we verified the predictive ability of these candidate lncRNAs in the testing set. Three glioma patient subgroups (cluster 1/2/3) were identified by consensus clustering. We further analysed the abundance of immune-infiltrating cells and the expression levels of immune checkpoint molecules in both three subgroups and two risk groups, respectively. Immunotherapy and anticancer drug response prediction showed that ER stress-related lncRNA risk signature positively correlates with responding to immune checkpoints and chemosensitivity. Functional analysis showed that these gene sets are enriched in the malignant process of tumors. Finally, LINC00519 was chosen for functional experiments. The silence of LINC00519 restrained the migration and invasion of glioma cells. Hence, those results indicated that ER stress-related lncRNA risk signature could be a potential treatment target and a prognosis biomarker for glioma patients.
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Affiliation(s)
- Yinfei Zheng
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Xiaoyu Yue
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Cheng Fang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Zhuang Jia
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Yuxiang Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Han Xie
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Jiajia Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Zhihao Yang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Lianxin Li
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Zhigang Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
| | - Erbao Bian
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
- *Correspondence: Erbao Bian, ; Bing Zhao,
| | - Bing Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, China
- *Correspondence: Erbao Bian, ; Bing Zhao,
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15
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Maires MPC, Pereira KR, Silva EKVB, Souza VHR, Teles F, Barbosa PF, Garnica MR, Ornellas FM, Noronha IL, Fanelli C. Synergic Renoprotective Effects of Combined ASC Therapy with RAAS Blockade in Experimental Advanced CKD. Stem Cells Int 2022; 2022:5111782. [PMID: 35371263 PMCID: PMC8975629 DOI: 10.1155/2022/5111782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/23/2022] [Indexed: 11/18/2022] Open
Abstract
Global prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis, contributes to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation/fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical, and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.
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Affiliation(s)
- Marina P. C. Maires
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Krislley R. Pereira
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Everidiene K. V. B. Silva
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Victor H. R. Souza
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Flavio Teles
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, State University of Health Sciences, Alagoas, Brazil
| | - Paulyana F. Barbosa
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, State University of Health Sciences, Alagoas, Brazil
| | - Margoth R. Garnica
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Felipe M. Ornellas
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Irene L. Noronha
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Camilla Fanelli
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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16
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Kongtasai T, Paepe D, Meyer E, Mortier F, Marynissen S, Stammeleer L, Defauw P, Daminet S. Renal biomarkers in cats: A review of the current status in chronic kidney disease. J Vet Intern Med 2022; 36:379-396. [PMID: 35218249 PMCID: PMC8965260 DOI: 10.1111/jvim.16377] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 12/22/2022] Open
Abstract
Serum creatinine concentration, the classical biomarker of chronic kidney disease (CKD) in cats, has important limitations that decrease its value as a biomarker of early CKD. Recently, serum symmetric dimethylarginine concentration was introduced as a novel glomerular filtration rate biomarker for the early detection of CKD in cats. However, data on its specificity are still limited. The limitations of conventional biomarkers and the desire for early therapeutic intervention in cats with CKD to improve outcomes have prompted the discovery and validation of novel renal biomarkers to detect glomerular or tubular dysfunction. Changes in the serum or urinary concentrations of these biomarkers may indicate early kidney damage or predict the progression of kidney before changes in conventional biomarkers are detectable. This review summarizes current knowledge on renal biomarkers in CKD in cats, a field that has progressed substantially over the last 5 years.
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Affiliation(s)
- Thirawut Kongtasai
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium.,Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Dominique Paepe
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium
| | - Evelyne Meyer
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Femke Mortier
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium
| | - Sofie Marynissen
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium
| | - Lisa Stammeleer
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium
| | - Pieter Defauw
- Lumbry Park Veterinary Specialists, Alton, United Kingdom
| | - Sylvie Daminet
- Small Animal Department, Faculty of Veterinary Science, Ghent University, Merelbeke, Belgium
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17
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Quimby J, Erickson A, Mcleland S, Cianciolo R, Maranon D, Lunn K, Elliott J, Lawson J, Hess A, Paschall R, Bailey S. Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease. Vet Sci 2021; 8:vetsci8120314. [PMID: 34941841 PMCID: PMC8703545 DOI: 10.3390/vetsci8120314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/12/2021] [Accepted: 12/02/2021] [Indexed: 01/15/2023] Open
Abstract
Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.
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Affiliation(s)
- Jessica Quimby
- Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.E.); (R.P.)
- Correspondence: ; Tel.: +1-614-292-3551
| | - Andrea Erickson
- Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.E.); (R.P.)
| | - Shannon Mcleland
- International Veterinary Renal Pathology Service, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA; (S.M.); (R.C.)
| | - Rachel Cianciolo
- International Veterinary Renal Pathology Service, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA; (S.M.); (R.C.)
| | - David Maranon
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80521-1618, USA; (D.M.); (S.B.)
| | - Katharine Lunn
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27695-0001, USA;
| | - Jonathan Elliott
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London E16 2PX, UK;
| | - Jack Lawson
- Department of Clinical Sciences and Services, Royal Veterinary College, Herts AL9 7TA, UK;
| | - Ann Hess
- Department of Statistics, Colorado State University, Fort Collins, CO 80521-4593, USA;
| | - Rene Paschall
- Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH 43210, USA; (A.E.); (R.P.)
| | - Susan Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80521-1618, USA; (D.M.); (S.B.)
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Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging. Acta Pharm Sin B 2021; 11:3665-3677. [PMID: 34900545 PMCID: PMC8642449 DOI: 10.1016/j.apsb.2021.05.013] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/26/2021] [Accepted: 05/05/2021] [Indexed: 12/22/2022] Open
Abstract
Detailed knowledge on tissue-specific metabolic reprogramming in diabetic nephropathy (DN) is vital for more accurate understanding the molecular pathological signature and developing novel therapeutic strategies. In the present study, a spatial-resolved metabolomics approach based on air flow-assisted desorption electrospray ionization (AFADESI) and matrix-assisted laser desorption ionization (MALDI) integrated mass spectrometry imaging (MSI) was proposed to investigate tissue-specific metabolic alterations in the kidneys of high-fat diet-fed and streptozotocin (STZ)-treated DN rats and the therapeutic effect of astragaloside IV, a potential anti-diabetic drug, against DN. As a result, a wide range of functional metabolites including sugars, amino acids, nucleotides and their derivatives, fatty acids, phospholipids, sphingolipids, glycerides, carnitine and its derivatives, vitamins, peptides, and metal ions associated with DN were identified and their unique distribution patterns in the rat kidney were visualized with high chemical specificity and high spatial resolution. These region-specific metabolic disturbances were ameliorated by repeated oral administration of astragaloside IV (100 mg/kg) for 12 weeks. This study provided more comprehensive and detailed information about the tissue-specific metabolic reprogramming and molecular pathological signature in the kidney of diabetic rats. These findings highlighted the promising potential of AFADESI and MALDI integrated MSI based metabolomics approach for application in metabolic kidney diseases.
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Key Words
- ADP, adenosine diphosphate
- AFADESI, air flow-assisted desorption electrospray ionization
- AGEs, advanced glycation end products
- AMP, adenosine monophosphate
- AMPK, adenosine monophosphate activated protein kinase
- AST, astragaloside IV
- ATP, adenosine triphosphate
- Astragaloside IV
- BUN, blood urea nitrogen
- CL, cardiolipin
- Cre, creatinine
- DAG, diacylglycerol
- DESI, desorption electrospray ionization
- DM, diabetes mellitus
- DN, diabetic nephropathy
- DPA, docosapentaenoic acid
- Diabetic nephropathy
- ESKD, end-stage kidney disease
- FBG, fasting blood glucose
- GLU, glucose
- GMP, guanosine monophosphate
- GSH, glutathione
- H&E, hematoxylin and eosin
- HPLC, high-performance liquid chromatography
- HbA1c, glycosylated hemoglobin
- LysoPC, lysophosphatidylcholine
- LysoPG, lysophosphatidylglycerol
- MALDI, matrix-assisted laser desorption ionization
- MS, mass spectrometry
- MSI, mass spectrometry imaging
- Mass spectrometry imaging
- Metabolic reprogramming
- NMR, nuclear magnetic resonance
- Na-CMC, sodium carboxymethyl cellulose
- PA, phosphatidic acid
- PC, phosphatidylcholine
- PE, phosphatidylethanolamine
- PG, phosphatidylglycerol
- PPP, pentose phosphate pathway
- PS, phosphatidylserine
- PUFA, polyunsaturated fatty acids
- ROI, regions of interest
- ROS, reactive oxygen species
- SDH, succinate dehydrogenase
- SGLTs, sodium-glucose cotransporters
- SM, sphingomyelin
- STZ, streptozotocin
- Spatial-resolved metabolomics
- TCA, tricarboxylic acid
- TCHO, total cholesterol
- TG, triglyceride
- UMP, uridine monophosphate
- VIP, variable importance in projection
- p-AMPK, phosphorylated adenosine monophosphate activated protein kinase
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19
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Boesen EI, Kakalij RM. Autoimmune-mediated renal disease and hypertension. Clin Sci (Lond) 2021; 135:2165-2196. [PMID: 34533582 PMCID: PMC8477620 DOI: 10.1042/cs20200955] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/20/2021] [Accepted: 09/06/2021] [Indexed: 12/18/2022]
Abstract
Hypertension is a major risk factor for cardiovascular disease, chronic kidney disease (CKD), and mortality. Troublingly, hypertension is highly prevalent in patients with autoimmune renal disease and hastens renal functional decline. Although progress has been made over the past two decades in understanding the inflammatory contributions to essential hypertension more broadly, the mechanisms active in autoimmune-mediated renal diseases remain grossly understudied. This Review provides an overview of the pathogenesis of each of the major autoimmune diseases affecting the kidney that are associated with hypertension, and describes the current state of knowledge regarding hypertension in these diseases and their management. Specifically, discussion focuses on Systemic Lupus Erythematosus (SLE) and Lupus Nephritis (LN), Immunoglobulin A (IgA) Nephropathy, Idiopathic Membranous Nephropathy (IMN), Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated glomerulonephritis, and Thrombotic Thrombocytopenic Purpura (TTP). A summary of disease-specific animal models found to exhibit hypertension is also included to highlight opportunities for much needed further investigation of underlying mechanisms and novel therapeutic approaches.
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Affiliation(s)
- Erika I Boesen
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
| | - Rahul M Kakalij
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, U.S.A
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20
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Wang M, Wang L, Zhou Y, Feng X, Ye C, Wang C. Icariin attenuates renal fibrosis in chronic kidney disease by inhibiting interleukin-1β/transforming growth factor-β-mediated activation of renal fibroblasts. Phytother Res 2021; 35:6204-6215. [PMID: 34426999 DOI: 10.1002/ptr.7256] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/08/2021] [Accepted: 08/10/2021] [Indexed: 12/21/2022]
Abstract
Icariin (ICA) is a bioactive flavonoid extracted from Epimedium brevicornum Maxim and exhibits a variety of pharmacological activities including antiinflammatory and antioxidant effects. Recently, icariin has shown renoprotective role by inhibiting pathological matrix. However, the underlying mechanisms of the efficacy remain unknown. This study aimed to determine the effects of icariin on renal fibrosis and explore its molecular mechanisms. Chronic kidney disease (CKD) was induced in rats with 5/6 ablation and infarction (A/I) operation. Four weeks later, rats were treated with vehicle or 20 mg/kg (low dose) or 40 mg/kg (high dose) of icariin by daily gavage. Furthermore, to further elucidate the effect mechanisms of icariin, in vitro, NRK-49F cells stimulated by 8 ng/ml IL-1β were treated with icariin in the presence or absence of SB431542 or the neutralizing antibody of transforming growth factor-β (TGF-β) for 24 h. We showed that icariin treatment for 8 weeks dose-dependently improved 5/6 (A/I)-induced kidney injury and fibrosis, and blocked the release of inflammatory cytokine IL-1β. In vitro, icariin inhibited IL-1β/TGF-β-mediated activation of renal fibroblasts. In summary, anti-fibrotic effects of icariin were interconnected with the inhibition of renal fibroblast activation caused by IL-1β/TGF-β signaling.
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Affiliation(s)
- Meng Wang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lingchen Wang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuan Zhou
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoxuan Feng
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chaoyang Ye
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chen Wang
- Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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21
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Kuang Q, Wu S, Xue N, Wang X, Ding X, Fang Y. Selective Wnt/β-Catenin Pathway Activation Concomitant With Sustained Overexpression of miR-21 is Responsible for Aristolochic Acid-Induced AKI-to-CKD Transition. Front Pharmacol 2021; 12:667282. [PMID: 34122087 PMCID: PMC8193720 DOI: 10.3389/fphar.2021.667282] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/13/2021] [Indexed: 01/09/2023] Open
Abstract
Acute kidney injury (AKI) is increasingly recognized as a cumulative risk factor for chronic kidney disease (CKD) progression. However, the underlying mechanisms remain unclear. Using an aristolochic acid (AA)-induced mouse model of AKI-to-CKD transition, we found that the development of tubulointerstitial fibrosis following AKI was accompanied with a strong activation of miR-21 and canonical Wnt signaling, whereas inhibition of miR-21 or selective silencing of Wnt ligands partially attenuated AKI-to-CKD transition. To explore the interaction between miR-21 and Wnt/β-catenin signaling, we examined the effects of genetic absence or pharmacologic inhibition of miR-21 on Wnt/β-catenin pathway expression. In miR-21-/- mice and in wild-type mice treated with anti-miR21 oligos, Wnt1 and Wnt4 canonical signaling in the renal tissue was significantly reduced, with partial reversal of renal interstitial fibrosis. Although the renal abundance of miR-21 remained unchanged after inhibition or activation of Wnt/β-catenin signaling, early intervention with ICG-001, a β-catenin inhibitor, significantly attenuated renal interstitial fibrosis. Moreover, early (within 24 h), but not late β-catenin inhibition after AA administration attenuated AA-induced apoptosis and inflammation. In conclusion, inhibition of miR-21 or β-catenin signaling may be an effective approach to prevent AKI-to-CKD progression.
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Affiliation(s)
- Qing Kuang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng Wu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Nephrology, Suzhou Dushuhu Public Hospital, Suzhou, China
| | - Ning Xue
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Xiaoyan Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoqianq Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
| | - Yi Fang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China
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22
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Kaplan A, Abidi E, Habeichi NJ, Ghali R, Alawasi H, Fakih C, Zibara K, Kobeissy F, Husari A, Booz GW, Zouein FA. Gender-biased kidney damage in mice following exposure to tobacco cigarette smoke: More protection in premenopausal females. Physiol Rep 2021; 8:e14339. [PMID: 31981316 PMCID: PMC6981307 DOI: 10.14814/phy2.14339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple clinical studies documented renal damage in chronic cigarette smokers (CS) irrespective of their age and gender. Premenopausal female smokers are known to exert a certain cardiovascular and renal protection with undefined mechanisms. Given the multiple demographic variables within clinical studies, this experimental study was designed to be the first to assess whether gender‐biased CS‐induced kidney damage truly exists between premenopausal female and age‐matched C57Bl6J male mice when compared to their relative control groups. Following 6 weeks of CS exposure, cardiac function, inflammatory marker production, fibrosis formation, total and glomerular ROS levels, and glomerulotubular homeostasis were assessed in both genders. Although both CS‐exposed male and female mice exhibited comparable ROS fold change relative to their respective control groups, CS‐exposed male mice showed a more pronounced fibrotic deposition, inflammation, and glomerulotubular damage profile. However, the protection observed in CS‐exposed female group was not absolute. CS‐exposed female mice exhibited a significant increase in fibrosis, ROS production, and glomerulotubular alteration but with a pronounced anti‐inflammatory profile when compared to their relative control groups. Although both CS‐exposed genders presented with altered glomerulotubular homeostasis, the alteration phenotype between genders was different. CS‐exposed males showed a significant decrease in Bowman's space along with reduced tubular diameter consistent with an endocrinization pattern of chronic tubular atrophy, suggestive of an advanced stage of glomerulotubular damage. CS‐exposed female group, on the other hand, displayed glomerular hypertrophy with a mild tubular dilatation profile suggestive of an early stage of glomerulotubular damage that generally precedes collapse. In conclusion, both genders are prone to CS‐induced kidney damage with pronounced female protection due to a milder damage slope.
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Affiliation(s)
- Abdullah Kaplan
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Emna Abidi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nada J Habeichi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rana Ghali
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hiam Alawasi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Christina Fakih
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Kazem Zibara
- Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ahmad Husari
- Department of Internal Medicine, Respiratory Diseases and Sleep Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - George W Booz
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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23
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Matyjek A, Literacki S, Niemczyk S, Rymarz A. Protein energy-wasting associated with nephrotic syndrome - the comparison of metabolic pattern in severe nephrosis to different stages of chronic kidney disease. BMC Nephrol 2020; 21:346. [PMID: 32795277 PMCID: PMC7427894 DOI: 10.1186/s12882-020-02003-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 08/03/2020] [Indexed: 01/29/2023] Open
Abstract
Background Nephrotic syndrome (NS) is associated with a hypercatabolic state expressed as an exacerbated degradation of muscle mass. However, the clinical significance of this phenomenon has not yet been investigated. The aim of the study was to evaluate the nutritional status of patients with severe NS (defined as nephrotic range proteinuria with hypoalbuminemia ≤2.5 g/dL) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in comparison to patients in different stages of chronic kidney disease (CKD). Methods Twenty men with severe NS (NS group) and 40 men without proteinuria similar in term of serum creatinine (control group) were included into the study. A retrospective cohort of 40 men with CKD stage G4 (PreD group) and 20 haemodialysis men (HD group) were added to the analysis after matching for age, height and weight using propensity score matching. The bioimpedance spectroscopy and biochemical nutritional markers were evaluated. Results Nephrotic patients had a significantly lower lean tissue mass (LTM; p = 0.035) and index (a quotient of LTM over height squared, LTI; p = 0.068), with an expected deficiency of LTM by 3.2 kg, and LTI by 0.9 kg/m2 when compared to the control group. A significant lean tissue deficit (defined as LTI below the lower limit of the reference range by 1.0 kg/m2) was observed in 12.5% of patients in the control group in comparison to 31.7% with advanced CKD (PreD+HD; p = 0.032) and 50% with NS (p = 0.003). NS group presented with higher phosphorus (p = 0.029), uric acid (p = 0.002) and blood urea (p = 0.049) than the control group. Blood urea was strongly negatively correlated with LTM in NS (r = − 0.64, p = 0.002). Nine nephrotic patients (45%) were identified as hypercatabolic based on severe hyperphosphatemia (> 5.0 mg/dL) and/or hyperuricemia (> 8.0 mg/dL), and were characterized by higher blood urea and lower prealbumin, as well as LTM lower by 5.6 kg than in less catabolic individuals. Conclusions In term of lean tissue amount, NS group was more similar to advanced CKD than to the control group. We concluded that specific metabolic pattern with elevated phosphorus, uric acid and blood urea, and lean tissue deficiency may be defined as protein-energy wasting associated with nephrotic syndrome (neph-PEW).
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Affiliation(s)
- Anna Matyjek
- Department of Internal Medicine, Nephrology and Dialysis, Military Institute of Medicine, Szaserów Street 128, 04-141, Warsaw, Poland.
| | - Slawomir Literacki
- Department of Laboratory Diagnostic, Military Institute of Medicine, Warsaw, Poland
| | - Stanislaw Niemczyk
- Department of Internal Medicine, Nephrology and Dialysis, Military Institute of Medicine, Szaserów Street 128, 04-141, Warsaw, Poland
| | - Aleksandra Rymarz
- Department of Internal Medicine, Nephrology and Dialysis, Military Institute of Medicine, Szaserów Street 128, 04-141, Warsaw, Poland
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24
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Sun H, Sun Z, Varghese Z, Guo Y, Moorhead JF, Unwin RJ, Ruan XZ. Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release. Am J Physiol Renal Physiol 2020; 319:F292-F303. [PMID: 32686520 DOI: 10.1152/ajprenal.00098.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a "first hit," while ATP itself is a "second hit" in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function.
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Affiliation(s)
- Hong Sun
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Endocrinology and Metabolism, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology and Metabolism, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Zac Varghese
- John Moorhead Research Laboratory, Department of Renal Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom
| | - Yinfeng Guo
- Department of Endocrinology and Metabolism, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - John F Moorhead
- John Moorhead Research Laboratory, Department of Renal Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom
| | - Robert John Unwin
- John Moorhead Research Laboratory, Department of Renal Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.,Early Cardiovascular, Renal & Metabolism, AstraZeneca Biopharmaceutical's R&D, Cambridge, United Kingdom
| | - Xiong Z Ruan
- John Moorhead Research Laboratory, Department of Renal Medicine, University College London Medical School, Royal Free Campus, London, United Kingdom.,Centre for Lipid Research and Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
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25
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White S, Lin L, Hu K. NF-κB and tPA Signaling in Kidney and Other Diseases. Cells 2020; 9:E1348. [PMID: 32485860 PMCID: PMC7348801 DOI: 10.3390/cells9061348] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis and progression of various human diseases including kidney, brain, and other diseases. Tissue plasminogen activator (tPA), a serine protease regulating homeostasis of blood coagulation, fibrinolysis, and matrix degradation, has been shown to act as a cytokine to trigger profound receptor-mediated intracellular events, modulate the NF-κB pathway, and mediate organ dysfunction and injury. In this review, we focus on the current understanding of NF-κB and tPA signaling in the development and progression of kidney disease. Their roles in the nervous and cardiovascular system are also briefly discussed.
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Affiliation(s)
| | - Ling Lin
- Nephrology Research Program, Department of Medicine, Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
| | - Kebin Hu
- Nephrology Research Program, Department of Medicine, Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA;
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26
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Li X, Bu X, Yan F, Wang F, Wei D, Yuan J, Zheng W, Su J, Yuan J. Deletion of discoidin domain receptor 2 attenuates renal interstitial fibrosis in a murine unilateral ureteral obstruction model. Ren Fail 2020; 41:481-488. [PMID: 31169440 PMCID: PMC6567249 DOI: 10.1080/0886022x.2019.1621759] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Background: Renal interstitial fibrosis is a common pathway of chronic kidney disease to end-stage renal disease, which is characterized by an imbalance between the synthesis and degradation of the collagen-rich extracellular matrix (ECM). While, discoidin domain receptor 2 (DDR2) can be activated when it binds to some types of collagen. Therefore, we hypothesized that DDR2 may be a major player in renal interstitial fibrosis. Methods: Renal histologic analysis, real-time PCR analyses and hydroxyproline assay were performed in DDR2-deficient mice and wild-type mice after unilateral ureteral obstruction; C57 mice were randomly divided into sham operation group (Sham group, n = 4), renal interstitial fibrosis model group (UUO group, n = 4), and calcium dobesilate treatment group (CDT group, n = 4), preparation of renal interstitial fibrosis model by unilateral ureteral obstruction (UUO), CDT Group was treated with calcium dobesilate orally, Sham group and UUO group were given double distilled water, HE staining, Masson staining, real-time quantitative PCR were detected after 14 days of UUO in mice to observe the renal interstitial fibrosis degree. Results: DDR2 expression was dramatically increased in the obstructed kidney; In contrast to wild-type mice that developed severe interstitial fibrosis, the DDR2-deficient mice displayed only moderate fibrotic changes; Compared with the UUO group, the degree of renal interstitial fibrosis in CDT group was relieved after operation 14 day. Conclusion: DDR2 might play an important role in the development of RIF; Calcium dobesilate can affect the expression of DDR2 and improve the renal interstitial fibrosis in mice.
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Affiliation(s)
- Xi'an Li
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Xin Bu
- b Department of Biochemistry and Molecular Biology , Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Fei Yan
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.,c Department of Gene Technology , Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Fuli Wang
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Di Wei
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Jiarui Yuan
- d Department of Biochemistry , University of Washington , Seattle , WA , USA
| | - Wanxiang Zheng
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Jin Su
- b Department of Biochemistry and Molecular Biology , Fourth Military Medical University , Xi'an , Shaanxi , China
| | - Jianlin Yuan
- a Department of Urology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China
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27
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Alves AF, Pereira RA, de Andrade HM, Mosser DM, Tafuri WL. Immunohistochemical study of renal fibropoiesis associated with dogs naturally and experimentally infected with two different strains of Leishmania (L.) infantum. Int J Exp Pathol 2019; 100:222-233. [PMID: 31696580 DOI: 10.1111/iep.12321] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 03/13/2019] [Accepted: 04/22/2019] [Indexed: 01/07/2023] Open
Abstract
The objectives of this work were to study some pathological aspects of kidneys obtained from dogs naturally infected with Leishmania infantum and from dogs experimentally infected with two different strains of L infantum with special emphasis on fibrotic process. Seventy eight specimens of paraffin-embedded kidney fragments were collected as follows: (a) CNI group composed by 62 kidney samples of adult mongrel dogs, naturally infected with L infantum; (b) BH401 group composed by five kidney samples of adult Beagles experimentally infected with L infantum strain MCAN BR/2002/BH401; (c) BH400 group composed by eleven kidney samples of adult Beagles experimentally infected with L infantum strain MCAN/BR/2000/BH400, at the same dose and same route of the previous group, denominated group BH400; Control group (CC) composed by four kidney samples of adult Beagles. All animals revealed glomerular and interstitial fibropoiesis associated with different types of glomerulonephritis and chronic interstitial nephritis. Fibrosis was markedly more intense in the BH401 group, followed by animals in the CNI group. Markers for myofibroblasts (mesenchymal markers) such as alpha-actin (α-SMA), vimentin and the cytokine transforming growth factor beta (TGF-β) were done by immunohistochemistry. BH401 group showed higher expression of all these markers than others. Intracellular amastigotes forms of Leishmania was mainly found in BH401. These results could be indicating that the MCAN/BR/2002/BH401 strain is a good choice for the study of renal LVC experimental model.
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Affiliation(s)
- Adriano F Alves
- Depto. de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ramon A Pereira
- Depto. de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Helida M de Andrade
- Depto. de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - David M Mosser
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland
| | - Wagner L Tafuri
- Depto. de Patologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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28
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Dan Q, Shi Y, Rabani R, Venugopal S, Xiao J, Anwer S, Ding M, Speight P, Pan W, Alexander RT, Kapus A, Szászi K. Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells. J Biol Chem 2019; 294:15446-15465. [PMID: 31481470 DOI: 10.1074/jbc.ra118.006484] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 08/21/2019] [Indexed: 12/19/2022] Open
Abstract
The tight junctional pore-forming protein claudin-2 (CLDN-2) mediates paracellular Na+ and water transport in leaky epithelia and alters cancer cell proliferation. Previously, we reported that tumor necrosis factor-α time-dependently alters CLDN-2 expression in tubular epithelial cells. Here, we found a similar expression pattern in a mouse kidney injury model (unilateral ureteral obstruction), consisting of an initial increase followed by a drop in CLDN-2 protein expression. CLDN-2 silencing in LLC-PK1 tubular cells induced activation and phosphorylation of guanine nucleotide exchange factor H1 (GEF-H1), leading to Ras homolog family member A (RHOA) activation. Silencing of other claudins had no such effects, and re-expression of an siRNA-resistant CLDN-2 prevented RHOA activation, indicating specific effects of CLDN-2 on RHOA. Moreover, kidneys from CLDN-2 knockout mice had elevated levels of active RHOA. Of note, CLDN-2 silencing reduced LLC-PK1 cell proliferation and elevated expression of cyclin-dependent kinase inhibitor P27 (P27KIP1) in a GEF-H1/RHOA-dependent manner. P27KIP1 silencing abrogated the effects of CLDN-2 depletion on proliferation. CLDN-2 loss also activated myocardin-related transcription factor (MRTF), a fibrogenic RHOA effector, and elevated expression of connective tissue growth factor and smooth muscle actin. Finally, CLDN-2 down-regulation contributed to RHOA activation and smooth muscle actin expression induced by prolonged tumor necrosis factor-α treatment, because they were mitigated by re-expression of CLDN-2. Our results indicate that CLDN-2 suppresses GEF-H1/RHOA. CLDN-2 down-regulation, for example, by inflammation, can reduce proliferation and promote MRTF activation through RHOA. These findings suggest that the initial CLDN-2 elevation might aid epithelial regeneration, and CLDN-2 loss could contribute to fibrotic reprogramming.
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Affiliation(s)
- Qinghong Dan
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Yixuan Shi
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Razieh Rabani
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Shruthi Venugopal
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Jenny Xiao
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Shaista Anwer
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Mei Ding
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Pam Speight
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada
| | - Wanling Pan
- Departments of Pediatrics and Physiology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - R Todd Alexander
- Departments of Pediatrics and Physiology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
| | - András Kapus
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada.,Department of Surgery, University of Toronto, Ontario M5B 1T8, Canada
| | - Katalin Szászi
- Keenan Research Centre for Biomedical Science at St. Michael's Hospital, University of Toronto, Ontario M5B 1T8, Canada .,Department of Surgery, University of Toronto, Ontario M5B 1T8, Canada
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Jia Y, Zheng Z, Xue M, Zhang S, Hu F, Li Y, Yang Y, Zou M, Li S, Wang L, Guan M, Xue Y. Extracellular Vesicles from Albumin-Induced Tubular Epithelial Cells Promote the M1 Macrophage Phenotype by Targeting Klotho. Mol Ther 2019; 27:1452-1466. [PMID: 31208912 DOI: 10.1016/j.ymthe.2019.05.019] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 05/16/2019] [Accepted: 05/21/2019] [Indexed: 12/22/2022] Open
Abstract
Albumin absorbed by renal tubular epithelial cells induces inflammation and plays a key role in promoting diabetic kidney disease (DKD) progression. Macrophages are prominent inflammatory cells in the kidney, and their role there is dependent on their phenotypes. However, whether albuminuria influences macrophage phenotypes and underlying mechanisms during the development of DKD is still unclear. We found that M1 macrophage-related markers were increased in diabetes mellitus (DM) mouse renal tissues with the development of DKD, and coculture of extracellular vesicles (EVs) from human serum albumin (HSA)-induced HK-2 cells with macrophages induced macrophage M1 polarization in the presence of lipopolysaccharide (LPS). Through a bioinformatic analysis, miR-199a-5p was selected and found to be increased in EVs from HSA-induced HK-2 cells and in urinary EVs from DM patients with macroalbuminuria. Tail-vein injection of DM mice with EVs from HSA-induced HK-2 cells induced kidney macrophage M1 polarization and accelerated the progression of DKD through miR-199a-5p. miR-199a-5p exerted its effect by targeting Klotho, and Klotho induced macrophage M2 polarization through the Toll-like receptor 4 (TLR4) pathway both in vivo and in vitro. In summary, miR-199a-5p from HSA-stimulated HK-2 cell-derived EVs induces M1 polarization by targeting the Klotho/TLR4 pathway and further accelerates the progression of DKD.
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Affiliation(s)
- Yijie Jia
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zongji Zheng
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meng Xue
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology and Metabolism, Shenzhen People's Hospital, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Shuting Zhang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fang Hu
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Yang Li
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanlin Yang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meina Zou
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuangshuang Li
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Wang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meiping Guan
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaoming Xue
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Chen W, Zhou ZQ, Ren YQ, Zhang L, Sun LN, Man YL, Wang ZK. Effects of long non-coding RNA LINC00667 on renal tubular epithelial cell proliferation, apoptosis and renal fibrosis via the miR-19b-3p/LINC00667/CTGF signaling pathway in chronic renal failure. Cell Signal 2019; 54:102-114. [DOI: 10.1016/j.cellsig.2018.10.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 10/24/2018] [Accepted: 10/25/2018] [Indexed: 10/28/2022]
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Tubulointerstitial Infiltration of M2 Macrophages in Henoch-Schönlein Purpura Nephritis Indicates the Presence of Glomerular Crescents and Bad Clinical Parameters. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8579619. [PMID: 30800680 PMCID: PMC6360621 DOI: 10.1155/2019/8579619] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 01/03/2019] [Indexed: 01/20/2023]
Abstract
Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and renal involvement (HSP nephritis, HSPN) is a severe manifestation. HSPN is histologically classified by the International Study of Kidney Disease in Children (ISKDC) based on mesangial hypercellularity and the extent of glomerular crescents. Macrophages, categorized as M1 or M2, frequently infiltrate in various glomerular and tubulointerstitial diseases and infiltration of specific subtypes is associated with disease progression. Therefore, to identify whether infiltration of M1 or M2 macrophages has clinical significance, we quantified the subtypes of macrophages in 49 HSPN specimens and correlated the counts with histologic features and clinical parameters. Higher tubulointerstitial M2 counts were associated with chronic renal failure (CRF), ISKDC classes III-IV, and crescents (P<0.001, 0.002, 0.001). Glomerular M2 counts were significantly related to ISKDC classes III-IV and crescents (area under curve, AUC 0.804, 0.833). Tubulointerstitial M2 counts were associated with CRF, ISKDC classes III-IV, and crescents (AUC 0.872, 0.778, 0.830). Tubulointerstitial M2 counts also revealed higher AUC than tubulointerstitial M1 counts for CRF (P=0.036) and ISKDC classes III-IV (P=0.047). Glomerular M2 counts revealed higher AUC than glomerular M1 counts for ISKDC classes III–IV (P=0.024). Tubulointerstitial M2 counts were the most powerful parameter for CRF (AUC 0.872) and revealed even higher AUC than ISKDC classification (AUC 0.716) with borderline significance (P=0.086) for CRF. In summary, tubulointerstitial M2 counts were a superior parameter to tubulointerstitial M1 counts and even to ISKDC classification indicating the presence of CRF.
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Zhu Y, Xu J, Liang W, Li J, Feng L, Zheng P, Ji T, Bai S. miR-98-5p Alleviated Epithelial-to-Mesenchymal Transition and Renal Fibrosis via Targeting Hmga2 in Diabetic Nephropathy. Int J Endocrinol 2019; 2019:4946181. [PMID: 31885559 PMCID: PMC6925681 DOI: 10.1155/2019/4946181] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/01/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Recently, microRNAs have been recognized as crucial regulators of diabetic nephropathy (DN) development. Epithelial-to-mesenchymal transition (EMT) can play a significant role in tubulointerstitial fibrosis, and it is a hallmark of diabetic nephropathy progression. Nevertheless, the function of miR-98-5p in the modulation of EMT and renal fibrosis during DN remains barely investigated. Hence, identifying the mechanisms of miR-98-5p in regulating EMT and fibrosis is of huge significance. In our present research, decreased miR-98-5p was demonstrated in db/db mice and mice mesangial cells treated with the high dose of glucose. Meanwhile, activated EMT and increased fibrosis was accompanied with the decrease of miR-98-5p in vitro and in vivo. Additionally, to further find out the roles of miR-98-5p in DN development, overexpression of miR-98-5p was applied. Firstly, in vivo investigation exhibited that elevation of miR-98-5p restrained proteinuria, serum creatinine, BUN, the EMT process, and fibrosis. Furthermore, high glucose was able to promote mice mesangial cell proliferation, EMT process, and induced renal fibrosis, which could be prevented by overexpression of miR-98-5p. Moreover, high mobility group A (HMGA2) can exhibit an important role in diverse biological processes. Here, HMGA2 was investigated as a target of miR-98-5p currently. Luciferase reporter assay was conducted and the correlation of miR-98-5p and HMGA2 was validated. Moreover, it was displayed that HMGA2 was remarkably elevated in db/db mice and mice mesangial cells. Furthermore, miR-98-5p strongly depressed HMGA2 protein and mRNA levels in mice mesangial cells. Overall, these revealed miR-98-5p could suppress the EMT process and renal fibrosis through targeting HMGA2 in DN.
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Affiliation(s)
- Yingchun Zhu
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - Jiang Xu
- Department of Rehabilitation, Huai'an Second People's Hospital, The Affiliated Hospital of Xuzhou Medical University, Huai'an, China
| | - Wenxing Liang
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - Ji Li
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - Linhong Feng
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - PengXi Zheng
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - Tingting Ji
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
| | - Shoujun Bai
- Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China
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Oliva-Damaso N, Oliva-Damaso E, Payan J. Acute and Chronic Tubulointerstitial Nephritis of Rheumatic Causes. Rheum Dis Clin North Am 2018; 44:619-633. [PMID: 30274627 DOI: 10.1016/j.rdc.2018.06.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Tubulointerstitial nephritis (TIN) is the second most common cause of acute intrinsic kidney injury after acute tubular necrosis. Although drug-induced forms of TIN represent the vast majority, rheumatic disease is another common cause and often underdiagnosed. Early diagnosis of acute interstitial nephritis and prompt withdrawal of the culprit medication or a correct treatment can avoid chronic damage and progressive chronic kidney disease. This review highlights the recent updates, clinical features, and treatment in TIN in autoimmune rheumatic disease.
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Affiliation(s)
- Nestor Oliva-Damaso
- Department of Medicine, Division of Nephrology, Hospital Costa del Sol, A-7, Km 187, 29305 Marbella, Malaga, Spain.
| | - Elena Oliva-Damaso
- Department of Medicine, Division of Nephrology, Hospital Doctor Negrin, Barranco de la Ballena, 35010 Las Palmas de Gran Canaria, Spain
| | - Juan Payan
- Department of Medicine, Division of Nephrology, Hospital Costa del Sol, A-7, Km 187, 29305 Marbella, Malaga, Spain
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Chrysin Inhibits Advanced Glycation End Products-Induced Kidney Fibrosis in Renal Mesangial Cells and Diabetic Kidneys. Nutrients 2018; 10:nu10070882. [PMID: 29987200 PMCID: PMC6073220 DOI: 10.3390/nu10070882] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 06/30/2018] [Accepted: 07/06/2018] [Indexed: 12/13/2022] Open
Abstract
Advanced glycation end products (AGEs) play a causative role in the development of diabetic nephropathy via induction of matrix protein deposition in kidneys. This study investigated inhibitory effects of chrysin, present in bee propolis and herbs, on glomerulosclerosis in db/db mice and AGEs-exposed renal mesangial cells. The in vivo study explored the demoting effects of 10 mg/kg chrysin on glomerular fibrosis in a type 2 diabetic model. Oral supplementation of chrysin inhibited the collagen fiber accumulation and α-smooth muscle actin (α-SMA) induction in periodic acid schiff-positive renal tissues of db/db mice. Moreover, treating db/db mice with chrysin diminished the level of AGEs increased in diabetic glomeruli. The in vitro study employed human mesangial cells exposed to 100 μg/mL AGE-BSA for 72 h in the presence of 1⁻20 μM chrysin. Glucose increased mesangial AGE production via induction of receptor for AGEs. Chrysin suppressed the induction of collagens, α-SMA, fibroblast-specific protein-1 and matrix metalloproteinases enhanced by AGE-bovine serum albumin. Furthermore, chrysin blunted transforming growth factor-β1 induction and Smad 2/3 activation in AGEs-exposed mesangial cells. These results demonstrate that chrysin attenuated accumulation of myofibroblast-like cells and matrix proteins in AGEs-laden diabetic glomeruli. Therefore, chrysin may be a potential renoprotective agent targeting glucose-mediated AGEs-associated glomerulosclerosis and fibrosis.
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35
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Black LM, Lever JM, Traylor AM, Chen B, Yang Z, Esman SK, Jiang Y, Cutter GR, Boddu R, George JF, Agarwal A. Divergent effects of AKI to CKD models on inflammation and fibrosis. Am J Physiol Renal Physiol 2018; 315:F1107-F1118. [PMID: 29897282 DOI: 10.1152/ajprenal.00179.2018] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with 99mTc-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 ( HMGB1), and colony stimulating factor-1 ( CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.
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Affiliation(s)
- L M Black
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - J M Lever
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - A M Traylor
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - B Chen
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Z Yang
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - S K Esman
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - Y Jiang
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - G R Cutter
- Department of Biostatistics, University of Alabama at Birmingham , Birmingham, Alabama
| | - R Boddu
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
| | - J F George
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.,Department of Surgery, University of Alabama at Birmingham , Birmingham, Alabama
| | - A Agarwal
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.,Department of Veterans Affairs , Birmingham, Alabama
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Zhang L, Xu C, Hu W, Wu P, Qin C, Zhang J. Anti-inflammatory effects of Lefty-1 in renal tubulointerstitial inflammation via regulation of the NF-κB pathway. Int J Mol Med 2017; 41:1293-1304. [PMID: 29286065 PMCID: PMC5819905 DOI: 10.3892/ijmm.2017.3327] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 11/23/2017] [Indexed: 11/13/2022] Open
Abstract
Renal tubulointerstitial inflammation has an important role in fibrosis, which is the main pathogenetic alteration associated with chronic kidney disease (CKD). The left-right determination factor 1 (Lefty-1) gene pleiotropically and biologically regulates transforming growth factor, mitogen-activated protein kinase and other signaling pathways, and is considered to have a potential anti-inflammatory function. However, its role in renal tubulointerstitial inflammation, which is often a long-term consequence of renal fibrosis, is currently unknown. In the present study, the effects of adenovirus-mediated overexpression of Lefty-1 (Ad-Lefty-1-flag) on renal tubulointerstitial inflammation were determined using a mouse model of unilateral ureteral obstruction (UUO) and a rat renal tubular duct epithelial cell line (NRK-52E), which was treated with lipopolysaccharide (LPS). In vivo results indicated that the inflammatory response was increased in UUO mice, as evidenced by the increase in inflammatory cytokines and chemokines. Conversely, Lefty-1 significantly reversed the effects of UUO. Furthermore, the results of the in vitro study demonstrated that Lefty-1 significantly inhibited LPS-induced inflammatory marker expression in cultured NRK-52E cells via the nuclear factor (NF)-κB signaling pathway. These results suggested that Lefty-1 may ameliorate renal tubulointerstitial inflammation by suppressing NF-κB signaling. In conclusion, the findings of the present study indicated that Lefty-1 may be considered a potential novel therapeutic agent for inhibiting renal tubulointerstitial inflammation or even reversing the CKD process.
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Affiliation(s)
- Lijun Zhang
- Department of Urology, Minda Hospital Affiliated to Hubei Institute for Nationalities, Enshi, Hubei 445000, P.R. China
| | - Changgeng Xu
- Department of Urology, Wuhan Central Hospital, Wuhan, Hubei 430014, P.R. China
| | - Wei Hu
- Department of Urology, The First Affiliated Hospital of University of South of China, Hengyang, Hunan 421001, P.R. China
| | - Pin Wu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Cong Qin
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jie Zhang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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37
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Bargi R, Asgharzadeh F, Beheshti F, Hosseini M, Farzadnia M, Khazaei M. Thymoquinone protects the rat kidneys against renal fibrosis. Res Pharm Sci 2017; 12:479-487. [PMID: 29204176 PMCID: PMC5691574 DOI: 10.4103/1735-5362.217428] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Thymoquinone (TQ) is the main active ingredient of Nigella sativa seeds with various pharmacological effects. The aim of this study was to investigate the effect of TQ on renal fibrosis and permeability and oxidative stress status in lipopolysaccharide (LPS)-induced inflammation in male rats. Eighty male Wistar rats were divided into 5 groups as follow: control (received normal saline), LPS (1 mg/kg/day), and LPS+TQ (by doses of 2, 5 and 10 mg/kg/day). After three weeks, the biochemical parameters such as blood urea nitrogen (BUN) and creatinine in serum samples, oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase (CAT) activities in renal tissue homogenate and renal permeability (evaluated by Evan's blue dye method) were measured and renal fibrosis was evaluated, histologically using Masson's trichrome staining. LPS administration induced renal fibrosis (1.49 ± 0.08 vs. 7.15 ± 0.18%) and significantly increased renal permeability (6.03 ± 1.05 vs. 13.5 ± 1.04 μg evans blue(EB)/g tissue), serum BUN and creatinine levels and oxidative stress marker (MDA) (P < 0.05), while, it reduced anti-oxidative markers including total thiol group, SOD and CAT activities (P < 0.05). Administration of TQ significantly improved these alterations which were dose-dependent in oxidative stress markers, renal permeability (TQ 2, 5 and 10 mg/kg: 10.7 ± 0.3, 9.2 ± 1.4 and 11.5 ± 0.6 μg EB/g tissue; respectively) and fibrosis (TQ 2, 5 and 10 mg/kg: 6.09 ± 0.7, 4.26 ± 0.14 and 2.52 ± 0.08%; respectively). In conclusion, administration of TQ reduced renal fibrosis and permeability and improved oxidative stress status. Thus, TQ can be considered in conditions accompanied with chronic inflammation at least as a part of treatment strategy.
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Affiliation(s)
- Rahimeh Bargi
- Department of Physiology and Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
| | - Fereshteh Asgharzadeh
- Department of Physiology and Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
| | - Farimah Beheshti
- Department of Physiology and Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
| | - Mahmoud Hosseini
- Neurocognitive Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
| | - Mehdi Farzadnia
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
| | - Majid Khazaei
- Department of Physiology and Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, I.R. Iran
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Tung CW, Hsu YC, Cai CJ, Shih YH, Wang CJ, Chang PJ, Lin CL. Trichostatin A ameliorates renal tubulointerstitial fibrosis through modulation of the JNK-dependent Notch-2 signaling pathway. Sci Rep 2017; 7:14495. [PMID: 29101337 PMCID: PMC5670251 DOI: 10.1038/s41598-017-15162-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 10/23/2017] [Indexed: 12/11/2022] Open
Abstract
Renal fibrosis is the final common pathological feature in a variety of chronic kidney disease. Trichostatin A (TSA), a histone deacetylase inhibitor, reportedly attenuates renal fibrosis in various kidney disease models. However, the detailed molecular action of TSA in ameliorating renal fibrotic injury is not yet fully understood. In a cultured renal fibroblastic cell model, we showed that TGF-β1 triggers upregulation of α-SMA and fibronectin, two hallmarks of myofibroblastic activation. During the course of TGF-β1 treatment, activation of Smad2/3, p38, ERK, JNK and Notch-2 was also detected. Under the conditions, administration of TSA significantly decreased TGF-β1-stimulated expression of α-SMA, fibronectin, phospho-JNK, and cleaved Notch-2; however, the levels of phospho-Smad2/3, phospho-p38 and phospho-ERK remained unchanged. Pharmacological inhibition of different signaling pathways and genetic knockdown of Notch-2 further revealed JNK as an upstream effector of Notch-2 in TGF-β1-mediated renal fibrosis. Consistently, we also demonstrated that administration of TSA or a γ-secretase inhibitor RO4929097 in the mouse model of unilateral ureteral obstruction significantly ameliorated renal fibrosis through suppression of the JNK/Notch-2 signaling activation. Taken together, our findings provide further insights into the crosstalk among different signaling pathways in renal fibrosis, and elucidate the molecular action of TSA in attenuating fibrogenesis.
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Affiliation(s)
- Chun-Wu Tung
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chang-Jhih Cai
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ya-Hsueh Shih
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ching-Jen Wang
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Pey-Jium Chang
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan. .,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan. .,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan. .,Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. .,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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39
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Cernaro V, Medici MA, Bianco F, Santoro D, Lacquaniti A, Romeo A, Lucisano S, Buemi A, Buemi M. Opposite actions of urotensin II and relaxin-2 on cellular expression of fibronectin in renal fibrosis: A preliminary experimental study. Clin Exp Pharmacol Physiol 2017; 44:1069-1071. [DOI: 10.1111/1440-1681.12798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 05/30/2017] [Accepted: 06/07/2017] [Indexed: 11/27/2022]
Affiliation(s)
- Valeria Cernaro
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Maria A Medici
- Department of Biological and Environmental Sciences; University of Messina; Messina Italy
| | - Federica Bianco
- Department of Biological and Environmental Sciences; University of Messina; Messina Italy
| | - Domenico Santoro
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Antonio Lacquaniti
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Adolfo Romeo
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Silvia Lucisano
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Antoine Buemi
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
| | - Michele Buemi
- Chair of Nephrology; Department of Clinical and Experimental Medicine; University of Messina; Messina Italy
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Mori da Cunha MGMC, Zia S, Beckmann DV, Carlon MS, Arcolino FO, Albersen M, Pippi NL, Graça DL, Gysemans C, Carmeliet P, Levtchenko E, Deprest J, Toelen J. Vascular Endothelial Growth Factor Up-regulation in Human Amniotic Fluid Stem Cell Enhances Nephroprotection After Ischemia-Reperfusion Injury in the Rat. Crit Care Med 2017; 45:e86-e96. [PMID: 27548820 DOI: 10.1097/ccm.0000000000002020] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To evaluate if the up-regulation of vascular endothelial growth factor strengthens the protective effect of amniotic fluid stem cells in a renal ischemia-reperfusion injury model. DESIGN Randomized animal study. SETTINGS University research laboratory. SUBJECTS A total of 40 males 12-week-old Wistar rats were subjected to ischemia-reperfusion and assigned to four groups: amniotic fluid stem cells, vascular endothelial growth factor-amniotic fluid stem cells in two different doses, and vehicle. Ten animals were used as sham-controls. INTERVENTION Six hours after induction of renal ischemia-reperfusion injury, amniotic fluid stem cells, vascular endothelial growth factor-amniotic fluid stem cells in two different doses, or vehicle were injected intraarterially. MEASUREMENTS AND MAIN RESULTS Analyses were performed at 24 hours, 48 hours, and 2 months after treatment. Outcome measures included serum creatinine, urine microprotenuira, and immunohistomorphometric analyses. Vascular endothelial growth factor-amniotic fluid stem cells induced a significantly higher nephroprotection than amniotic fluid stem cells. This effect was mediated mainly by immunomodulation, which led to lower macrophage infiltration and higher presence of regulatory T cell after ischemia-reperfusion injury. At medium term, it inhibited the progression toward chronic kidney disease. Vascular endothelial growth factor-amniotic fluid stem cells can worsen the ischemia-reperfusion injury when delivered in a high dose. CONCLUSIONS Up-regulation of vascular endothelial growth factor enhances the therapeutic effect of human amniotic fluid stem cells in rats with renal ischemia-reperfusion injury, mainly by mitogenic, angiogenic, and anti-inflammatory mechanisms.
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Affiliation(s)
- Marina Gabriela Monteiro Carvalho Mori da Cunha
- 1Department of Development and Regeneration, Organ System Cluster, Fetal Therapy group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium. 2Experimental Veterinary Surgery Laboratory, Department of Small Animals, Universidade Federal de Santa Maria, Santa Maria, Brazil. 3Department of Pharmaceutical and Pharmacological Sciences, Molecular Virology and Gene Therapy, Group Biomedical Sciences, KU Leuven, Leuven, Belgium. 4Department of Development and Regeneration, Organ System Cluster, Laboratory of Pediatric Nephrology, Group Biomedical Sciences, KU Leuven, Leuven, Belgium. 5Department of Urology, University Hospitals Leuven, Leuven, Belgium. 6Department of Clinical and Experimental Medicine, Clinical and Experimental Endocrinology, Leuven, Belgium. 7Department of Oncology, Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, KU Leuven, Leuven, Belgium. 8Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium. 9Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
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Luque Y, Cathelin D, Vandermeersch S, Xu X, Sohier J, Placier S, Xu-Dubois YC, Louis K, Hertig A, Bories JC, Vasseur F, Campagne F, Di Santo JP, Vosshenrich C, Rondeau E, Mesnard L. Glomerular common gamma chain confers B- and T-cell–independent protection against glomerulonephritis. Kidney Int 2017; 91:1146-1158. [DOI: 10.1016/j.kint.2016.10.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 10/19/2016] [Accepted: 10/27/2016] [Indexed: 12/22/2022]
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Zhao Y, Yin Z, Li H, Fan J, Yang S, Chen C, Wang DW. MiR-30c protects diabetic nephropathy by suppressing epithelial-to-mesenchymal transition in db/db mice. Aging Cell 2017; 16:387-400. [PMID: 28127848 PMCID: PMC5334541 DOI: 10.1111/acel.12563] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2016] [Indexed: 12/24/2022] Open
Abstract
Epithelial‐to‐mesenchymal transition (EMT) plays a significant role in tubulointerstitial fibrosis, which is a hallmark of diabetic nephropathy. Thus, identifying the mechanisms of EMT activation could be meaningful. In this study, loss of miR‐30c accompanied with increased EMT was observed in renal tubules of db/db mice and cultured HK2 cells exposed to high glucose. To further explore the roles of miR‐30c in EMT and tubulointerstitial fibrosis, recombinant adeno‐associated viral vector was applied to manipulate the expression of miR‐30c. In vivo study showed that overexpression of miR‐30c suppressed EMT, attenuated renal tubulointerstitial fibrosis and reduced proteinuria, serum creatinine, and BUN levels. In addition, Snail1 was identified as a direct target of miR‐30c by Ago2 co‐immunoprecipitation, luciferase reporter, and Western blot assays. Downregulating Snail1 by siRNA reduced high glucose‐induced EMT in HK2 cells, and miR‐30c mimicked the effects. Moreover, miR‐30c inhibited Snail1‐TGF‐β1 axis in tubular epithelial cells undergoing EMT and thereby impeded the release of TGF‐β1; oppositely, knockdown of miR‐30c enhanced the secretion of TGF‐β1 from epitheliums and significantly promoted proliferation of fibroblasts and fibrogenesis of myofibroblasts, aggravated tubulointerstitial fibrosis, and dysfunction of diabetic nephropathy. These results suggest a protective role of miR‐30c against diabetic nephropathy by suppressing EMT via inhibiting Snail1‐TGF‐β1 pathway.
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Affiliation(s)
- Yanru Zhao
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
| | - Zhongwei Yin
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
| | - Huaping Li
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
| | - Jiahui Fan
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
| | - Shenglan Yang
- Department of Cardiology; The First Affiliated Hospital of Chongqing Medical University; Chongqing 400042 China
| | - Chen Chen
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
| | - Dao Wen Wang
- Division of Cardiology; Department of Internal Medicine; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430030 China
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Perazella MA. Clinical Approach to Diagnosing Acute and Chronic Tubulointerstitial Disease. Adv Chronic Kidney Dis 2017; 24:57-63. [PMID: 28284380 DOI: 10.1053/j.ackd.2016.08.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 07/18/2016] [Accepted: 08/15/2016] [Indexed: 11/11/2022]
Abstract
Tubulointerstitial diseases are a relatively common cause of acute and/or chronic kidney disease. Acute tubulointerstitial nephritis (ATIN) most commonly develops in patients exposed to various medications; however, it can occur from infections, autoimmune and systemic diseases, environmental exposures, and some idiopathic causes. Chronic tubulointerstitial nephritis may develop in patients with previous ATIN or may be the initial manifestation of an autoimmune, systemic, environmental, or metabolic process. It can be challenging for clinicians to differentiate the various causes of acute and chronic kidney disease. In particular, distinguishing ATIN from other causes of acute kidney injury, such as acute tubular necrosis or a rapidly progressive glomerulonephritis, is important as treatment and prognosis are often quite different. To this end, clinicians use clinical assessment, certain laboratory data, and various imaging tests to make a diagnosis. Unfortunately, most of these tests are insufficient for this purpose. As a result, kidney biopsy is often required to accurately diagnose ATIN and guide management. For chronic tubulointerstitial nephritis, kidney biopsy is needed less often as available therapies for this entity, with a few exceptions, are limited and primarily supportive.
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44
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Nast CC. Medication-Induced Interstitial Nephritis in the 21st Century. Adv Chronic Kidney Dis 2017; 24:72-79. [PMID: 28284382 DOI: 10.1053/j.ackd.2016.11.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/21/2016] [Accepted: 11/21/2016] [Indexed: 01/19/2023]
Abstract
Interstitial nephritis is an immune mediated form of tubulointerstitial kidney injury that may occur secondary to drugs, autoimmune disease, infections, and hematologic disorders or as a reactive process. Drug-induced acute interstitial nephritis (DI-AIN) occurs in 0.5%-3% of all kidney biopsies and in 5%-27% of biopsies performed for acute kidney injury. Drugs are implicated in 70%-90% of biopsy-proved IN with a prevalence of 50% in less developed to 78% in more developed countries. DI-AIN typically is idiosyncratic because of a delayed hypersensitivity reaction, although some chemotherapeutic agents are permissive for immune upregulation and injure the kidney in a dose-related manner. Antibiotics are the most implicated class of medication in DI-AIN, followed by proton pump inhibitors, nonsteroidal anti-inflammatory agents, and 5-aminosalicylates. Diuretics, allopurinol, phenytoin and other anti-seizure medications, and H2 receptor antagonists are known offenders while chemotherapeutic agents are an under-recognized cause. The symptoms of DI-AIN are variable and often not specific; thus, kidney biopsy is required to make a firm diagnosis. The incidence of DI-AIN appears to be increasing, particularly in the elderly in whom kidney biopsy is underused, and identification of the offending agent may be complicated by polypharmacy. As rapid drug discontinuation may improve prognosis, the possibility of DI-AIN should always be considered in a patient with acute kidney injury.
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45
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Chi HH, Hua KF, Lin YC, Chu CL, Hsieh CY, Hsu YJ, Ka SM, Tsai YL, Liu FC, Chen A. IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis. J Am Soc Nephrol 2017; 28:2022-2037. [PMID: 28179433 DOI: 10.1681/asn.2016080840] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 01/04/2017] [Indexed: 12/19/2022] Open
Abstract
IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36α expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36α in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36α facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.
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Affiliation(s)
| | - Kuo-Feng Hua
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and
| | | | - Ching-Liang Chu
- Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Yu Hsieh
- Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and
| | - Yu-Juei Hsu
- Division of Nephrology, Department of Medicine
| | - Shuk-Man Ka
- Graduate Institutes of Life Sciences and .,Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | | | - Feng-Cheng Liu
- Division of Rheumatology/Immunology and Allergy, Department of Medicine, and
| | - Ann Chen
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan;
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Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2. Mediators Inflamm 2016; 2016:5802973. [PMID: 27843201 PMCID: PMC5097817 DOI: 10.1155/2016/5802973] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 09/27/2016] [Indexed: 11/18/2022] Open
Abstract
Indoxyl sulfate (IS) is one of important uremic toxins and is markedly accumulated in the circulation of end stage renal disease (ESRD) patients, which might contribute to the damage of residual nephrons and progressive loss of residual renal function (RRF). Thus this study was undertaken to investigate the role of IS in modulating mesangial cell (MC) proliferation and the underlying mechanism. The proliferation of MCs induced by IS was determined by cell number counting, DNA synthase rate, and cell cycle phase analysis. COX-2 expression was examined by Western blotting and qRT-PCR, and a specific COX-2 inhibitor NS398 was applied to define its role in IS-induced MC proliferation. Following IS treatment, MCs exhibited increased total cell number, DNA synthesis rate, and number of cells in S and G2 phases paralleled with the upregulation of cyclin A2 and cyclin D1. Next, we found an inducible inflammation-related enzyme COX-2 was remarkably enhanced by IS, and the inhibition of COX-2 by NS398 significantly blocked IS-induced MC proliferation in line with a blockade of PGE2 production. These findings indicated that IS could induce MC proliferation via a COX-2-mediated mechanism, providing new insights into the understanding and therapies of progressive loss of RRF in ESRD.
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Mann JFE, Rossing P, Wiȩcek A, Rosivall L, Mark P, Mayer G. Diagnosis and treatment of early renal disease in patients with type 2 diabetes mellitus: what are the clinical needs? Nephrol Dial Transplant 2016. [PMID: 26209731 DOI: 10.1093/ndt/gfv120] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Renal disease is prevalent in patients with diabetes mellitus type 2. Aggressive metabolic control and lowering of systemic and/or intraglomerular blood pressure are effective interventions but not without side effects. Thus a better, early identification of patients at risk for incidence or progression to end-stage renal failure by the use of new, validated biomarkers is highly desirable. In the majority of patients, hypertension and hyperglycaemia are pathogenetically important pathways for the progression of renal disease. Nonetheless even aggressive therapy targeting these factors does not eliminate the risk of end-stage renal failure and experimental evidence suggests that many other pathways (e.g. tubulointerstitial hypoxia or inflammation etc.) also contribute. As their individual importance might vary from patient to patient, interventions which interfere are likely not to be therapeutically effective in all subjects. In this situation, an option to preserve the statistical power of clinical trials is to rely on biomarkers that reflect individual pathophysiology. In current clinical practice, albuminuria is the biomarker that has been best evaluated to guide stratified/personalized therapy but there is a clear need to expand our diagnostic abilities.
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Affiliation(s)
- Johannes F E Mann
- Department of Medicine IV, Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | | | - Andrzej Wiȩcek
- Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland
| | - László Rosivall
- Institute of Pathophysiology, International Nephrology Research and Training Center Semmelweis University, Budapest, Hungary
| | - Patrick Mark
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Gert Mayer
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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48
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Yu J, Gong W, Wu Y, Li S, Cui Y, Ma Y, Zhang Y, Yang G, Huang S, Jia Z, Zhang A. mPGES-1-derived PGE2 contributes to adriamycin-induced podocyte injury. Am J Physiol Renal Physiol 2016; 310:F492-8. [PMID: 26739892 DOI: 10.1152/ajprenal.00499.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/04/2016] [Indexed: 12/21/2022] Open
Abstract
Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL-1β and TNF-α were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF-α, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response.
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Affiliation(s)
- Jing Yu
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Wei Gong
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Yimei Wu
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Shuzhen Li
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Yiyun Cui
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Yifei Ma
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Yue Zhang
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Guangrui Yang
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Songming Huang
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Zhanjun Jia
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
| | - Aihua Zhang
- Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and
- Nanjing Key Laboratory of Pediatrics, Nanjing, China
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Lowenstine LJ, McManamon R, Terio KA. Comparative Pathology of Aging Great Apes: Bonobos, Chimpanzees, Gorillas, and Orangutans. Vet Pathol 2015; 53:250-76. [PMID: 26721908 DOI: 10.1177/0300985815612154] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The great apes (chimpanzees, bonobos, gorillas, and orangutans) are our closest relatives. Despite the many similarities, there are significant differences in aging among apes, including the human ape. Common to all are dental attrition, periodontitis, tooth loss, osteopenia, and arthritis, although gout is uniquely human and spondyloarthropathy is more prevalent in apes than humans. Humans are more prone to frailty, sarcopenia, osteoporosis, longevity past reproductive senescence, loss of brain volume, and Alzheimer dementia. Cerebral vascular disease occurs in both humans and apes. Cardiovascular disease mortality increases in aging humans and apes, but coronary atherosclerosis is the most significant type in humans. In captive apes, idiopathic myocardial fibrosis and cardiomyopathy predominate, with arteriosclerosis of intramural coronary arteries. Similar cardiac lesions are occasionally seen in wild apes. Vascular changes in heart and kidneys and aortic dissections in gorillas and bonobos suggest that hypertension may be involved in pathogenesis. Chronic kidney disease is common in elderly humans and some aging apes and is linked with cardiovascular disease in orangutans. Neoplasms common to aging humans and apes include uterine leiomyomas in chimpanzees, but other tumors of elderly humans, such as breast, prostate, lung, and colorectal cancers, are uncommon in apes. Among the apes, chimpanzees have been best studied in laboratory settings, and more comparative research is needed into the pathology of geriatric zoo-housed and wild apes. Increasing longevity of humans and apes makes understanding aging processes and diseases imperative for optimizing quality of life in all the ape species.
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Affiliation(s)
- L J Lowenstine
- Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA, USA Mountain Gorilla Veterinary Project-Gorilla Doctors, Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - R McManamon
- Zoo and Exotic Animal Pathology Service, Infectious Diseases Laboratory, Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - K A Terio
- Zoological Pathology Program, University of Illinois College of Veterinary Medicine, Maywood, IL, USA
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50
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Garrido P, Ribeiro S, Fernandes J, Vala H, Rocha-Pereira P, Bronze-da-Rocha E, Belo L, Costa E, Santos-Silva A, Reis F. Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia. Int J Mol Sci 2015; 17:ijms17010028. [PMID: 26712750 PMCID: PMC4730274 DOI: 10.3390/ijms17010028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 11/23/2015] [Accepted: 12/18/2015] [Indexed: 12/21/2022] Open
Abstract
This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.
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Affiliation(s)
- Patrícia Garrido
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Sandra Ribeiro
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - João Fernandes
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - Helena Vala
- Center for Studies in Education, and Health Technologies, CI&DETS, CITAB, Agrarian School of Viseu, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal.
| | - Petronila Rocha-Pereira
- Research Centre in Health Sciences, University of Beira Interior, 6201-001 Covilhã, Portugal.
| | - Elsa Bronze-da-Rocha
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - Luís Belo
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - Elísio Costa
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - Alice Santos-Silva
- UCIBIO@REQUIMTE, Faculty of Pharmacy, Department of Biological Sciences, Laboratory of Biochemistry, University of Porto, 4050-313 Porto, Portugal.
| | - Flávio Reis
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Consortium, University of Coimbra, 3000-548 Coimbra, Portugal.
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