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Marrapu S, Kumar R. Transition from acute kidney injury to chronic kidney disease in liver cirrhosis patients: Current perspective. World J Nephrol 2025; 14:102381. [DOI: 10.5527/wjn.v14.i1.102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/22/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
In liver cirrhosis patients, acute kidney injury (AKI) is a common and severe complication associated with significant morbidity and mortality, often leading to chronic kidney disease (CKD). This progression reflects a complex interplay of renal and hepatic pathophysiology, with AKI acting as an initiator through maladaptive repair mechanisms. These mechanisms—such as tubular cell cycle arrest, inflammatory cascades, and fibrotic processes—are exacerbated by the hemodynamic and neurohormonal disturbances characteristic of cirrhosis. Following AKI episodes, persistent kidney dysfunction or acute kidney disease (AKD) often serves as a bridge to CKD. AKD represents a critical phase in renal deterioration, characterized by prolonged kidney injury that does not fully meet CKD criteria but exceeds the temporal scope of AKI. The progression from AKD to CKD is further influenced by recurrent AKI episodes, impaired renal autoregulation, and systemic comorbidities such as diabetes and metabolic dysfunction-associated steatotic liver disease, which compound kidney damage. The clinical management of AKI and CKD in cirrhotic patients requires a multidimensional approach that includes early identification of kidney injury, the application of novel biomarkers, and precision interventions. Recent evidence underscores the inadequacy of traditional biomarkers in predicting the AKI-to-CKD progression, necessitating novel biomarkers for early detection and intervention.
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Affiliation(s)
- Sudheer Marrapu
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Li Y, Luo Y, Hu Y, Li S, Li G, Zhang W, Gu X, Wang J, Li S, Cheng H. Network pharmacology and multi-omics validation of the Jianpi-Yishen formula in the treatment of chronic kidney disease. Front Immunol 2025; 15:1512519. [PMID: 39877349 PMCID: PMC11772200 DOI: 10.3389/fimmu.2024.1512519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/19/2024] [Indexed: 01/31/2025] Open
Abstract
Objective Chronic kidney disease (CKD) is a major global health problem. In clinical practice, the Chinese patent herbal medicine Jianpi-Yishen (JPYS) formula is commonly used to treat CKD. However, the molecular mechanisms by which JPYS targets and modulates the host immune response remain unclear. Methods This study utilized network pharmacology, RNA sequencing (RNA-seq), and metabolic analyses using in vivo and in vitro models to investigate the impact of the JPYS formula on inflammation and the immune system. Specifically, the study focused on macrophage polarization and metabolic changes that may slow down the progression of CKD. Results A total of 14,946 CKD-related targets were identified from the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases through network pharmacology analyses. 227 potential targets of the JPYS formula were predicted using the TCMSP database. Additionally, network diagram demonstrated that 11 targets were associated with macrophage activity. In vivo studies indicated that the JPYS formula could reduce blood urea nitrogen and serum creatinine in adenine-induced CKD rats. Furthermore, the formula inhibited inflammatory damage and abnormal macrophage infiltration in this CKD model. RNA-seq, proteomic and metabolic analyses identified the regulation of amino acid metabolism by betaine, specifically referring to glycine, serine, and threonine metabolism, as a key target of the JPYS formula in slowing the progression of CKD. In addition, in vitro studies suggested that JPYS may enhance tryptophan metabolism in M1 macrophage polarization and betaine metabolism in M2 macrophage polarization. Conclusions The JPYS formula has been shown to have beneficial impact on CKD; a key mechanism is the mitigation of inflammatory damage through the interaction between amino acid metabolism and macrophage polarization. Of specific importance in this context are the roles of tryptophan in M1 polarization and betaine in M2 polarization.
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Affiliation(s)
- Yuyan Li
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yueming Luo
- Department of Geriatrics, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yilan Hu
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Siting Li
- Beijing Tongrentang Hospital of Traditional Chinese Medicine, Beijing, China
| | - Guandong Li
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wanyangchuan Zhang
- Department of Minimally Invasive Intervention and Vascular Surgery, Chongqing Red Cross Hospital (People’s Hospital of Jiangbei District), Chongqing, China
| | - Xiufen Gu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jianting Wang
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Shunmin Li
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Hong Cheng
- Department of Geriatrics, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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Yang S, Ye Z, Chen L, Zhou X, Li W, Cheng F. Circadian Clock Gene Bmal1: A Molecular Bridge from AKI to CKD. Biomolecules 2025; 15:77. [PMID: 39858471 PMCID: PMC11762869 DOI: 10.3390/biom15010077] [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: 10/31/2024] [Revised: 12/05/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) represent two frequently observed clinical conditions. AKI is characterized by an abrupt decrease in glomerular filtration rate (GFR), generally associated with elevated serum creatinine (sCr), blood urea nitrogen (BUN), and electrolyte imbalances. This condition usually persists for approximately a week, causing a transient reduction in kidney function. If these abnormalities continue beyond 90 days, the condition is redefined as chronic kidney disease (CKD) or may advance to end-stage renal disease (ESRD). Recent research increasingly indicates that maladaptive repair mechanisms after AKI significantly contribute to the development of CKD. Thus, implementing early interventions to halt the progression from AKI to CKD has the potential to markedly improve patient outcomes. Although considerable research has been conducted, the exact mechanisms linking AKI to CKD are complex, and effective treatments remain limited. Kidney function is influenced by circadian rhythms, with the circadian gene Bmal1 being vital in managing these cycles. Recent research indicates that Bmal1 is significantly involved in the progression of both AKI and CKD. In this study, we conducted a retrospective analysis of Bmal1's role in AKI and CKD, reviewed recent research advancements, and investigated how Bmal1 influences the pathological mechanisms underlying the progression from AKI to CKD. Additionally, we highlighted gaps in the existing research and examined the potential of Bmal1 as a therapeutic target in kidney disease management. This work aims to provide meaningful insights for future studies on the role of the circadian gene Bmal1 in the transition from AKI to CKD, with the goal of identifying therapeutic approaches to mitigate kidney disease progression.
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Affiliation(s)
- Songyuan Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (L.C.); (X.Z.)
| | - Zehua Ye
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (L.C.); (X.Z.)
| | - Lijia Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (L.C.); (X.Z.)
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (L.C.); (X.Z.)
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (L.C.); (X.Z.)
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Jeong K, Je J, Dusabimana T, Karekezi J, Nugroho TA, Ndahigwa EN, Kim HJ, Yun SP, Kim HJ, Kim H, Park SW. Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice. Sci Rep 2024; 14:31932. [PMID: 39738595 DOI: 10.1038/s41598-024-83411-6] [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: 09/19/2024] [Accepted: 12/13/2024] [Indexed: 01/02/2025] Open
Abstract
Chronic kidney disease is defined as a progressive loss of kidney function associated with impaired recovery after acute kidney injury. Renal ischemia-reperfusion (IR) induces oxidative stress and inflammatory responses leading to severe tissue damage, where incomplete or maladaptive repair accelerates renal fibrosis and aging. To investigate the role of the purinergic P2Y2 receptor (P2Y2R) in these processes, we used P2Y2R knockout (KO) mice subjected to IR. KO mice showed severe kidney dysfunction and structural damage compared to WT mice. KO mice showed higher senescence-associated β-galactosidase expression and shorter telomere length than WT mice. Consistently, interstitial collagen accumulation and fibrogenic mediators were significantly upregulated in KO mice. Renal apoptosis and inflammation were highly elevated in KO mice. Interestingly, cell proliferation as shown by Ki-67 and PCNA expression, was increased for 3 days after IR in WT mice, whereas it maintained increased for 14 days in KO mice. Cell cycle inhibitors, p16 and p21, and regulators JunB and cyclin E were significantly increased after IR in KO mice, suggesting that cell cycle progression was impaired during recovery after IR. Proximal tubular cells treated with JunB siRNA showed a reduced expression of fibrogenic mediators and proinflammatory cytokines, consistent with the mice treated with MRS2768, a P2Y2 agonist that downregulated JunB levels. In conclusion, P2Y2R reduces kidney tissue damage after IR and repairs the tissue properly by regulating JunB-mediated signaling during the recovery process.
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Affiliation(s)
- Kyuho Jeong
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Jihyun Je
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
| | - Theodomir Dusabimana
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
| | - Jacques Karekezi
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Tatang Aldi Nugroho
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Edvard Ntambara Ndahigwa
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hyun Joon Kim
- Department of Anatomy, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Seung Pil Yun
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hye Jung Kim
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hwajin Kim
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea.
| | - Sang Won Park
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea.
- Department of Anatomy, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, 52727, Republic of Korea.
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Zhang T, Widdop RE, Ricardo SD. Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers. Am J Physiol Renal Physiol 2024; 327:F788-F805. [PMID: 39298548 DOI: 10.1152/ajprenal.00184.2024] [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: 06/26/2024] [Revised: 08/15/2024] [Accepted: 09/01/2024] [Indexed: 09/22/2024] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions with overlapping pathophysiological mechanisms. This review examines the transition from AKI to CKD, focusing on the molecular mechanisms, animal models, and biomarkers essential for understanding and managing this progression. AKI often progresses to CKD due to maladaptive repair processes, persistent inflammation, and fibrosis, with both conditions sharing common pathways involving cell death, inflammation, and extracellular matrix (ECM) deposition. Current animal models, including ischemia-reperfusion injury (IRI) and nephrotoxic damage, help elucidate these mechanisms but have limitations in replicating the complexity of human disease. Emerging biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble tumor necrosis factor receptors (TNFRs) show promise in early detection and monitoring of disease progression. This review highlights the need for improved animal models and biomarker validation to better mimic human disease and enhance clinical translation. Advancing our understanding of the AKI-to-CKD transition through targeted therapies and refined research approaches holds the potential to significantly improve patient outcomes.
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Affiliation(s)
- Tingfang Zhang
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Robert E Widdop
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sharon D Ricardo
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
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Xue JL, Ji JL, Zhou Y, Zhang Y, Liu BC, Ma RX, Li ZL. The multifaceted effects of mitochondria in kidney diseases. Mitochondrion 2024; 79:101957. [PMID: 39270830 DOI: 10.1016/j.mito.2024.101957] [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: 06/10/2024] [Revised: 08/23/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024]
Abstract
Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.
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Affiliation(s)
- Jia-Le Xue
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jia-Ling Ji
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Zhou
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yao Zhang
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Rui-Xia Ma
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
| | - Zuo-Lin Li
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
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Lee SY, Park JM, Rhim WK, Lee EH, Lee SH, Kim JY, Cha SG, Lee SH, Kim B, Hwang DY, Rho S, Ahn TK, Kim BS, Han DK. Multifunctional extracellular vesicles and edaravone-loaded scaffolds for kidney tissue regeneration by activating GDNF/RET pathway. NANO CONVERGENCE 2024; 11:43. [PMID: 39460807 PMCID: PMC11512987 DOI: 10.1186/s40580-024-00450-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024]
Abstract
With the severity of chronic kidney disease worldwide, strategies to recover renal function via tissue regeneration provide alternatives to kidney replacement therapy. To exclude side effects from direct cell transplantation, extracellular vesicles (EVs) are great substitutes representing paracrine cell signaling. To build three-dimensional structures for implantation into the 5/6 nephrectomy model by incorporating bioactive materials, including multifunctional EVs (mEVs), porous PMEZE/mEV scaffolds were developed in combination with edaravone (EDV; E) and mEV based on PMEZ scaffolds with PLGA (P), MH-RA (M), ECM (E), ZnO-ALA (Z). The oxygen free radical scavenger EDV was incorporated to induce tubular regeneration. mEVs were engineered to serve regenerative activities with a combination of two EVs from SDF-1α overexpressed tonsil-derived mesenchymal stem cells (sEVs) and intermediate mesoderm (IM) cells during differentiation into kidney progenitor cells (dEVs). mEVs displayed beneficial effects on regeneration by facilitating migration and inducing differentiation of surrounding stem cells, and EDV improved kidney function by regulating the GDNF/RET pathway and their downstream genes. The promotion of MSC recruitment was confirmed with sEV particles number dependently, and the regulation of the GDNF/RET pathway by the effect of EDV and its enhanced effect by mEVs were elucidated using in vitro analysis. The regeneration of tubules was additionally demonstrated through the increased expression of aquaporin-1 (AQP-1) and cadherin-16 (CDH16) for proximal tubules, and calbindin and PAX2 for distal tubules in the renal defect model. With these, structural regeneration and functional recovery were achieved with kidney regeneration in the 5/6 nephrectomy mice model.
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Affiliation(s)
- Seung Yeon Lee
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Jeong Min Park
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Won-Kyu Rhim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Eun Hye Lee
- Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-Gu, Daegu, 41944, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Microbiology, School of Medicine, CHA University, Seongnam, Gyeonggi-Do, 13496, Republic of Korea
| | - Jun Yong Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Seung-Gyu Cha
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Sun Hong Lee
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Boram Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea
| | - Dong-Youn Hwang
- Department of Microbiology, School of Medicine, CHA University, Seongnam, Gyeonggi-Do, 13496, Republic of Korea
| | - Seungsoo Rho
- Department of Ophthalmology, CHA Bundang Medical Center, CHA University, 59 Yatap-Ro, Bundang-Gu, Seongnam, Gyeonggi-Do, 13496, Republic of Korea
| | - Tae-Keun Ahn
- Department of Orthopedic Surgery CHA Bundang Medical Center, CHA University, Seonnam, Gyeonggi-Do, 13496, Republic of Korea
| | - Bum Soo Kim
- Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-Gu, Daegu, 41944, Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-Do, 13488, Republic of Korea.
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Bhat AA, Moglad E, Afzal M, Thapa R, Almalki WH, Kazmi I, Alzarea SI, Ali H, Pant K, Singh TG, Dureja H, Singh SK, Dua K, Gupta G, Subramaniyan V. Therapeutic approaches targeting aging and cellular senescence in Huntington's disease. CNS Neurosci Ther 2024; 30:e70053. [PMID: 39428700 PMCID: PMC11491556 DOI: 10.1111/cns.70053] [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: 05/29/2024] [Revised: 08/09/2024] [Accepted: 09/06/2024] [Indexed: 10/22/2024] Open
Abstract
Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," and "CELLULAR SENESCENCE." Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as "DNA DAMAGE," "OXIDATIVE STRESS," and "AUTOPHAGY." According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro-inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients' quality of life.
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Affiliation(s)
- Asif Ahmad Bhat
- Uttaranchal Institute of Pharmaceutical SciencesUttaranchal UniversityDehradunIndia
| | - Ehssan Moglad
- Department of Pharmaceutics, College of PharmacyPrince Sattam Bin Abdulaziz UniversityAl KharjSaudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy ProgramBatterjee Medical CollegeJeddahSaudi Arabia
| | - Riya Thapa
- Uttaranchal Institute of Pharmaceutical SciencesUttaranchal UniversityDehradunIndia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of PharmacyUmm Al‐Qura UniversityMakkahSaudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of ScienceKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Sami I. Alzarea
- Department of Pharmacology, College of PharmacyJouf UniversitySakakaAl‐JoufSaudi Arabia
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical SciencesSaveetha UniversityChennaiIndia
- Department of PharmacologyKyrgyz State Medical CollegeBishkekKyrgyzstan
| | - Kumud Pant
- Graphic Era (Deemed to be University), Dehradun, India
| | | | - Harish Dureja
- Department of Pharmaceutical SciencesMaharshi Dayanand UniversityRohtakIndia
| | - Sachin Kumar Singh
- School of Pharmaceutical SciencesLovely Professional UniversityPhagwaraPunjabIndia
- Faculty of Health, Australian Research Centre in Complementary and Integrative MedicineUniversity of Technology SydneyUltimoNew South WalesAustralia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative MedicineUniversity of Technology SydneyUltimoNew South WalesAustralia
- Discipline of Pharmacy, Graduate School of HealthUniversity of Technology SydneySydneyNew South WalesAustralia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of PharmacyChitkara UniversityRajpuraPunjabIndia
- Centre of Medical and Bio‐Allied Health Sciences ResearchAjman UniversityAjmanUnited Arab Emirates
| | - Vetriselvan Subramaniyan
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health SciencesMonash UniversityBandar SunwaySelangor Darul EhsanMalaysia
- Department of Medical SciencesSchool of Medical and Life Sciences Sunway UniversityBandar SunwaySelangor Darul EhsanMalaysia
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He M, Niu J, Cheng H, Guo C. Identification and validation of diagnostic genes associated with neutrophil extracellular traps of type 2 diabetes mellitus. Front Genet 2024; 15:1373807. [PMID: 39296548 PMCID: PMC11408200 DOI: 10.3389/fgene.2024.1373807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 08/20/2024] [Indexed: 09/21/2024] Open
Abstract
Background Neutrophil extracellular traps (NETs) cause delayed wound closed up in type 2 diabetes mellitus (T2DM), but the specific regulatory mechanism of NETs-related genes (NETs-RGs) in T2DM is unclear. Methods We acquired GSE21321 and GSE15932 datasets from gene expression omnibus (GEO) database. First, differentially expressed genes (DEGs) between T2DM and control samples of GSE21321 dataset were sifted out by differential expression analysis. NETs scores were calculated for all samples in GSE21321 dataset, and key module genes associated with NETs scores were screened by constructing co-expression network. Then, DEGs and key module genes were intersected to yield intersection genes, and candidate genes were identified by constructing a protein protein interaction (PPI) network. Least absolute shrinkage and selection operator (LASSO) regression analysis was implemented on candidate genes to screen out diagnostic genes, and they were subjected to single sample gene set enrichment analysis (ssGSEA). Finally, immune characteristic analysis was carried out, and we constructed the gene-drug and transcription factor (TF)-miRNA-mRNA networks. Besides, we validated the expression of diagnostic genes by quantitative real-time polymerase chain reaction (qRT-PCR). Results In total, 23 candidate genes were gained by PPI analysis. The 5 diagnostic genes, namely, inter-trypsin inhibitor heavy chain 3 (ITIH3), fibroblast growth factor 1 (FGF1), neuron cell adhesion molecule (NRCAM), advanced glycosylation end-product-specific receptor (AGER), and calcium voltage-gated channel subunit alpha1 C (CACNA1C), were identified via LASSO analysis, and they were involved in carboxylic acid transport, axonogenesis, etc. M2 Macrophage, Monocyte, Natural killer (NK) cell, and Myeloid dendritic cells (DC) were remarkably different between T2DM and control samples. Diagnostic genes had the strongest and the most significant positive correlation with B cells. The gene-drug network included CACNA1C-Isradipine, CACNA1C-Benidipine and other relationship pairs. Totally 76 nodes and 44 edges constituted the TF-miRNA-mRNA network, including signal transducer and activator of transcription 1(STAT1) -hsa-miR-3170-AGER, CCCTC-binding factor (CTCF)-hsa-miR-455-5p-CACNA1C, etc. Moreover, qRT-PCR suggested that the expression trends of FGF1 and AGER were in keeping with the results of bioinformatic analysis. FGF1 and AGER were markedly regulated downwards in the T2DM group. Conclusion Through bioinformatic analysis, we identified NETs-related diagnostic genes (ITIH3, FGF1, NRCAM, AGER, CACNA1C) in T2DM, and explored their mechanism of action from different aspects, providing new ideas for the studies related to diagnosis and treatment of T2DM.
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Affiliation(s)
- Meifang He
- Endocrinoloy Department, Peking University First Hospital Taiyuan Hospital (Taiyuan Central Hospital), Taiyuan, China
| | - Jin Niu
- Endocrinoloy Department, Peking University First Hospital Taiyuan Hospital (Taiyuan Central Hospital), Taiyuan, China
| | - Haihua Cheng
- Endocrinoloy Department, Peking University First Hospital Taiyuan Hospital (Taiyuan Central Hospital), Taiyuan, China
| | - Chaoying Guo
- Endocrinoloy Department, Peking University First Hospital Taiyuan Hospital (Taiyuan Central Hospital), Taiyuan, China
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10
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Salybekov AA, Okamura S, Ohtake T, Hidaka S, Asahara T, Kobayashi S. Extracellular Vesicle Transplantation Is Beneficial for Acute Kidney Injury. Cells 2024; 13:1335. [PMID: 39195224 PMCID: PMC11352623 DOI: 10.3390/cells13161335] [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: 07/15/2024] [Revised: 08/03/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
Under vasculogenic conditioning, certain pro-inflammatory subsets within peripheral blood mononuclear cells (PBMCs) undergo phenotypic transformation into pro-regenerative types, such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells. These transformed cells are collectively termed regeneration-associated cells (RACs). In this study, we aimed to investigate the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared with a vehicle-treated group in the context of renal ischemia-reperfusion injury (R-IRI). Human PBMCs were cultured with defined growth factor cocktails for seven days to harvest RACs. EV quantity and size were characterized by nanoparticle tracking analysis. Notably, the systemic injection of RACev significantly decreased serum creatinine and blood urine nitrogen at day three compared to the control group. Histologically, the treatment group showed less fibrosis in the cortex and medullary areas (p < 0.04 and p < 0.01) compared to the control group. The CD31 staining confirmed enhanced capillary densities in the treatment group compared to the control group (p < 0.003). These beneficial effects were accompanied by angiogenesis, anti-fibrosis, anti-inflammation, and anti-apoptosis RACev miR delivery to ischemic injury to control inflammatory, endothelial mesenchymal transition, and hypoxia pathways. In vivo bioluminescence analysis demonstrated a preferential accumulation of RACev in the IR-injured kidney. The systemic transplantation of RACev beneficially restored kidney function by protecting from tissue fibrosis and through anti-inflammation, angiogenesis, and anti-apoptosis miR delivery to the ischemic tissue.
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Affiliation(s)
- Amankeldi A. Salybekov
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (T.O.); (S.H.); (S.K.)
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
| | - Shigeaki Okamura
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
| | - Takayasu Ohtake
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (T.O.); (S.H.); (S.K.)
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
- Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Okamoto 1-1370, Kamakura 2478533, Japan
| | - Sumi Hidaka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (T.O.); (S.H.); (S.K.)
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
| | - Takayuki Asahara
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (T.O.); (S.H.); (S.K.)
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan; (S.O.); (T.A.)
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11
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Lu Y, Xie XN, Xin QQ, Yuan R, Miao Y, Cong WH, Chen KJ. Advance on Chinese Medicine for Hypertensive Renal Damage: Focus on the Complex Molecular Mechanisms. Chin J Integr Med 2024:10.1007/s11655-024-3662-3. [PMID: 38958884 DOI: 10.1007/s11655-024-3662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 07/04/2024]
Abstract
Hypertensive renal damage (HRD) is a major cause of end-stage renal disease. Among the causes of end-stage renal disease, HRD accounts for nearly 34% of the total number of cases. Antihypertensive treatment is primarily drug-based, but therapeutic efficacy is less effective and can have serious side effects. Chinese medicine (CM) has significant advantages in the treatment of HRD. CM is rich in various active ingredients and has the property of targeting multiple targets and channels. Therefore, the regulatory network of CM on disease is complex. A large number of CM have been employed to treat HRD, either as single applications or as part of compound formulations. The key possible mechanisms of CM for HRD include regulation of the renin-angiotensin-aldosterone system, antioxidation, anti-inflammation, rescue of endothelial function, regulation of vasoactive substance secretion and obesity-related factors, etc. This review summarized and discussed the recent advance in the basic research mechanisms of CM interventions for HRD and pointed out the challenges and future prospects.
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Affiliation(s)
- Yan Lu
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Xue-Na Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau, 999078, China
| | - Qi-Qi Xin
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Rong Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Yu Miao
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
| | - Wei-Hong Cong
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China.
| | - Ke-Ji Chen
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, 100091, China
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12
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Li T, Yang K, Tong Y, Guo S, Gao W, Zou X. Targeted Drug Therapy for Senescent Cells Alleviates Unilateral Ureteral Obstruction-Induced Renal Injury in Rats. Pharmaceutics 2024; 16:695. [PMID: 38931822 PMCID: PMC11206309 DOI: 10.3390/pharmaceutics16060695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hydronephrosis resulting from unilateral ureteral obstruction (UUO) is a common cause of renal injury, often progressing to late-stage renal fibrosis or even potential renal failure. Renal injury and repair processes are accompanied by changes in cellular senescence phenotypes. However, the mechanism is poorly understood. The purpose of this study is to clarify the changes in senescence phenotype at different time points in renal disease caused by UUO and to further investigate whether eliminating senescent cells using the anti-senescence drug ABT263 could attenuate UUO-induced renal disease. Specifically, renal tissues were collected from established UUO rat models on days 1, 2, 7, and 14. The extent of renal tissue injury and fibrosis in rats was assessed using histological examination, serum creatinine, and blood urea nitrogen levels. The apoptotic and proliferative capacities of renal tissues and phenotypic changes in cellular senescence were evaluated. After the intervention of the anti-senescence drug ABT263, the cellular senescence as well as tissue damage changes were re-assessed. We found that before the drug intervention, the UUO rats showed significantly declined renal function, accompanied by renal tubular injury, increased inflammatory response, and oxidative stress, alongside aggravated cellular senescence. Meanwhile, after the treatment with ABT263, the rats had a significantly lower number of senescent cells, attenuated renal tubular injury and apoptosis, enhanced proliferation, reduced oxidative stress and inflammation, improved renal function, and markedly inhibited fibrosis. This suggests that the use of the anti-senescence drug ABT263 to eliminate senescent cells can effectively attenuate UUO-induced renal injury. This highlights the critical role of cellular senescence in the transformation of acute injury into chronic fibrosis.
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Affiliation(s)
| | | | | | | | - Wei Gao
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang 261053, China; (T.L.); (K.Y.); (Y.T.); (S.G.)
| | - Xiangyu Zou
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang 261053, China; (T.L.); (K.Y.); (Y.T.); (S.G.)
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13
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Koh ES, Chung S. Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease Transition. Yonsei Med J 2024; 65:247-256. [PMID: 38653563 PMCID: PMC11045347 DOI: 10.3349/ymj.2023.0306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/27/2023] [Accepted: 01/23/2024] [Indexed: 04/25/2024] Open
Abstract
Acute kidney injury (AKI) is characterized by an abrupt decline of excretory kidney function. The incidence of AKI has increased in the past decades. Patients diagnosed with AKI often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from AKI to chronic kidney disease (CKD). Although recent clinical studies have demonstrated a strong association between AKI and progression of CKD, our understanding of the complex relationship between AKI and CKD is still evolving. No cohort study has succeeded in painting a comprehensive picture of these multi-faceted pathways. To address this lack of understanding, the idea of acute kidney disease (AKD) has recently been proposed. This presents a new perspective to pinpoint a period of heightened vulnerability following AKI, during which a patient could witness a substantial decline in glomerular filtration rate, ultimately leading to CKD transition. Although AKI is included in a range of kidney conditions collectively known as AKD, spanning from mild and self-limiting to severe and persistent, AKD can also occur without a rapid onset usually seen in AKI, such as when kidney dysfunction slowly evolves. In the present review, we summarize the most recent findings about AKD, explore the current state of biomarker discovery related to AKD, discuss the latest insights into pathophysiological underpinnings of AKI to CKD transition, and reflect on therapeutic challenges and opportunities that lie ahead.
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Affiliation(s)
- Eun Sil Koh
- Division of Nephrology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sungjin Chung
- Division of Nephrology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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14
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Li T, Yang K, Gao W, Peng F, Zou X. Cellular senescence in acute kidney injury: Target and opportunity. Biochem Biophys Res Commun 2024; 706:149744. [PMID: 38479244 DOI: 10.1016/j.bbrc.2024.149744] [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: 12/07/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/24/2024]
Abstract
Acute kidney injury (AKI) is a common clinical disease with a high incidence and mortality rate. It typically arises from hemodynamic alterations, sepsis, contrast agents, and toxic drugs, instigating a series of events that culminate in tissue and renal damage. This sequence of processes often leads to acute renal impairment, prompting the initiation of a repair response. Cellular senescence is an irreversible arrest of the cell cycle. Studies have shown that renal cellular senescence is closely associated with AKI through several mechanisms, including the promotion of oxidative stress and inflammatory response, telomere shortening, and the down-regulation of klotho expression. Exploring the role of cellular senescence in AKI provides innovative therapeutic ideas for both the prevention and treatment of AKI. Furthermore, it has been observed that targeted removal of senescent cells in vivo can efficiently postpone senescence, resulting in an enhanced prognosis for diseases associated with senescence. This article explores the effects of common anti-senescence drugs senolytics and senostatic and lifestyle interventions on renal diseases, and mentions the rapid development of mesenchymal stem cells (MSCs). These studies have taken senescence-related research to a new level. Overall, this article comprehensively summarizes the studies on cellular senescence in AKI, aiming is to elucidate the relationship between cellular senescence and AKI, and explore treatment strategies to improve the prognosis of AKI.
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Affiliation(s)
- Ting Li
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China.
| | - Kexin Yang
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Wei Gao
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Fujun Peng
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Xiangyu Zou
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China.
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15
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Elshoff D, Mehta P, Ziouzenkova O. Chronic Kidney Disease Diets for Kidney Failure Prevention: Insights from the IL-11 Paradigm. Nutrients 2024; 16:1342. [PMID: 38732588 PMCID: PMC11085624 DOI: 10.3390/nu16091342] [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: 03/22/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Nearly every fifth adult in the United States and many older adults worldwide are affected by chronic kidney disease (CKD), which can progress to kidney failure requiring invasive kidney replacement therapy. In this review, we briefly examine the pathophysiology of CKD and discuss emerging mechanisms involving the physiological resolution of kidney injury by transforming growth factor beta 1 (TGFβ1) and interleukin-11 (IL-11), as well as the pathological consequences of IL-11 overproduction, which misguides repair processes, ultimately culminating in CKD. Taking these mechanisms into account, we offer an overview of the efficacy of plant-dominant dietary patterns in preventing and managing CKD, while also addressing their limitations in terms of restoring kidney function or preventing kidney failure. In conclusion, this paper outlines novel regeneration strategies aimed at developing a reno-regenerative diet to inhibit IL-11 and promote repair mechanisms in kidneys affected by CKD.
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Affiliation(s)
- Denise Elshoff
- School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH 43210, USA;
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA;
| | - Priyanka Mehta
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA;
| | - Ouliana Ziouzenkova
- Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA;
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16
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Jacobs ME, de Vries DK, Engelse MA, Dumas SJ, Rabelink TJ. Endothelial to mesenchymal transition in kidney fibrosis. Nephrol Dial Transplant 2024; 39:752-760. [PMID: 37968135 DOI: 10.1093/ndt/gfad238] [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: 09/04/2023] [Indexed: 11/17/2023] Open
Abstract
Fibrotic diseases are characterized by the uncontrolled accumulation of extracellular matrix (ECM) components leading to disruption of tissue homeostasis. Myofibroblasts as the main ECM-producing cells can originate from various differentiated cell types after injury. Particularly, the process of endothelial-to-mesenchymal transition (endMT), describing phenotypic shifts of endothelial cells to adopt a fully mesenchymal identity, may contribute to the pool of myofibroblasts in fibrosis, while leading to capillary rarefaction and exacerbation of tissue hypoxia. In renal disease, incomplete recovery from acute kidney injury (AKI) and the ensuing fibrotic reaction stand out as major contributors to chronic kidney disease (CKD) development. While the focus has largely been on impaired tubular epithelial repair as a potential fibrosis-driving mechanism, alterations in the renal microcirculation post-AKI, and in particular endMT as a maladaptive response, could hold equal significance. Dysfunctional interplays among various cell types in the kidney microenvironment can instigate endMT. Transforming growth factor beta (TGF-β) signaling, with its downstream activation of canonical/Smad-mediated and non-canonical pathways, has been identified as primary driver of this process. However, non-TGF-β-mediated pathways involving inflammatory agents and metabolic shifts in intercellular communication within the tissue microenvironment can also trigger endMT. These harmful, maladaptive cell-cell interactions and signaling pathways offer potential targets for therapeutic intervention to impede endMT and decelerate fibrogenesis such as in AKI-CKD progression. Presently, partial reduction of TGF-β signaling using anti-diabetic drugs or statins may hold therapeutic potential in renal context. Nevertheless, further investigation is warranted to validate underlying mechanisms and assess positive effects within a clinical framework.
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Affiliation(s)
- Marleen E Jacobs
- Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Dorottya K de Vries
- Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Marten A Engelse
- Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Sébastien J Dumas
- Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Ton J Rabelink
- Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
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17
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Yu C, Tang J, Yu J, Wang Y, Liu N, Dong Z, Zhuang S. JMJD3 activation contributes to renal protection and regeneration following acute kidney injury in mice. FASEB J 2024; 38:e23583. [PMID: 38551634 DOI: 10.1096/fj.202300681r] [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: 04/08/2023] [Revised: 03/04/2024] [Accepted: 03/18/2024] [Indexed: 04/02/2024]
Abstract
We have recently demonstrated that Jumonji domain-containing protein D3 (JMJD3), a histone demethylase of histone H3 on lysine 27 (H3K27me3), is protective against renal fibrosis, but its role in acute kidney injury (AKI) remains unexplored. Here, we report that JMJD3 activity is required for renal protection and regeneration in murine models of AKI induced by ischemia/reperfusion (I/R) and folic acid (FA). Injury to the kidney upregulated JMJD3 expression and induced expression of H3K27me3, which was coincident with renal dysfunction, renal tubular cell injury/apoptosis, and proliferation. Blocking JMJD3 activity by GSKJ4 led to worsening renal dysfunction and pathological changes by aggravating tubular epithelial cell injury and apoptosis in both murine models of AKI. JMJD3 inhibition by GSKJ4 also reduced renal tubular cell proliferation and suppressed expression of cyclin E and phosphorylation of CDK2, but increased p21 expression in the injured kidney. Furthermore, inactivation of JMJD3 enhanced I/R- or FA-induced expression of TGF-β1, vimentin, and Snail, phosphorylation of Smad3, STAT3, and NF-κB, and increased renal infiltration by F4/80 (+) macrophages. Finally, GSKJ4 treatment caused further downregulation of Klotho, BMP-7, Smad7, and E-cadherin, all of which are associated with renal protection and have anti-fibrotic effects. Therefore, these data provide strong evidence that JMJD3 activation contributes to renal tubular epithelial cell survival and regeneration after AKI.
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Affiliation(s)
- Chao Yu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinhua Tang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianjun Yu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanjin Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA
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18
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Zhang D, Liu S, Jiang H, Liu S, Kong F. DIA proteomics analysis reveals the mechanism of folic acid-induced acute kidney injury and the effects of icariin. Chem Biol Interact 2024; 390:110878. [PMID: 38272249 DOI: 10.1016/j.cbi.2024.110878] [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: 12/01/2023] [Revised: 01/04/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024]
Abstract
The complexities of acute kidney injury (AKI), a multifaceted pathological occurrence, are not fully understood. At present, there is a lack of effective pharmaceutical treatments in clinical practice. Studies have shown that icariin has beneficial effects in models of acute kidney injury (AKI) caused by cisplatin and lipopolysaccharide (LPS). The aim is to explore the mechanisms that cause folic acid (FA)-induced AKI and examine the protective effects of icariin against this condition. To establish a mouse model of AKI, FA was administered via intraperitoneal injection. Icariin was used as the drug intervention. The model and the impact of drug intervention were assessed using measurements of renal function parameters, staining with hematoxylin and eosin, and Q-PCR. The analysis of protein expression changes in the control, model, and icariin treatment groups was conducted using proteomics. KEGG signaling pathway analysis indicates that differential expressed proteins are enriched in the component and coagulation cascades signaling pathway. Through protein-protein interaction network analysis, it was found that compared to the normal group, the expression of Fibrinogen and other proteins was significantly upregulated at the center of the protein interaction network in the model group. After drug treatment, the expression of these proteins was significantly downregulated. The validation experiment supports the above results. In conclusion, this study clarified the molecular mechanism of FA induced acute renal injury from the proteomics level, and provided target selection for AKI; At the same time, the mechanism of icariin in the treatment of AKI was analyzed from the proteomics level.
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Affiliation(s)
- Denglu Zhang
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shuai Liu
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China; Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huihui Jiang
- Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shuangde Liu
- Department of Kidney Transplantation, Multidisciplinary Innovation Center for Nephrology, The Second Hospital of Shandong University, Jinan, China.
| | - Feng Kong
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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19
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Chen J, Zhang H, Yi X, Dou Q, Yang X, He Y, Chen J, Chen K. Cellular senescence of renal tubular epithelial cells in acute kidney injury. Cell Death Discov 2024; 10:62. [PMID: 38316761 PMCID: PMC10844256 DOI: 10.1038/s41420-024-01831-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/14/2024] [Accepted: 01/24/2024] [Indexed: 02/07/2024] Open
Abstract
Cellular senescence represents an irreversible state of cell-cycle arrest during which cells secrete senescence-associated secretory phenotypes, including inflammatory factors and chemokines. Additionally, these cells exhibit an apoptotic resistance phenotype. Cellular senescence serves a pivotal role not only in embryonic development, tissue regeneration, and tumor suppression but also in the pathogenesis of age-related degenerative diseases, malignancies, metabolic diseases, and kidney diseases. The senescence of renal tubular epithelial cells (RTEC) constitutes a critical cellular event in the progression of acute kidney injury (AKI). RTEC senescence inhibits renal regeneration and repair processes and, concurrently, promotes the transition of AKI to chronic kidney disease via the senescence-associated secretory phenotype. The mechanisms underlying cellular senescence are multifaceted and include telomere shortening or damage, DNA damage, mitochondrial autophagy deficiency, cellular metabolic disorders, endoplasmic reticulum stress, and epigenetic regulation. Strategies aimed at inhibiting RTEC senescence, targeting the clearance of senescent RTEC, or promoting the apoptosis of senescent RTEC hold promise for enhancing the renal prognosis of AKI. This review primarily focuses on the characteristics and mechanisms of RTEC senescence, and the impact of intervening RTEC senescence on the prognosis of AKI, aiming to provide a foundation for understanding the pathogenesis and providing potentially effective approaches for AKI treatment.
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Affiliation(s)
- Juan Chen
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Huhai Zhang
- Department of Nephrology, Southwest Hospital, Army Medical University, 400042, Chongqing, China
| | - Xiangling Yi
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Qian Dou
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Xin Yang
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Yani He
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China
| | - Jia Chen
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China.
| | - Kehong Chen
- Department of Nephrology, Daping Hospital, Army Medical University, 400042, Chongqing, China.
- State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China.
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20
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Yue J, Bao X, Meng LF. PROTECTIVE ROLE OF MELATONIN FOR ACUTE KIDNEY INJURY: A SYSTEMATIC REVIEW AND META-ANALYSIS. Shock 2024; 61:167-174. [PMID: 38010077 DOI: 10.1097/shk.0000000000002278] [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: 11/29/2023]
Abstract
ABSTRACT Introduction : Acute kidney injury (AKI) is an important clinical issue that arouses global concerns, which puzzles clinicians and lacks effective drug treatment for AKI until the present. Melatonin has been well recognized to modulate the sleep-wake cycle and had the renal protective effect. However, there are still few clinical trials investigating the relationship between melatonin and AKI. The conclusions drawn in existing clinical studies are still inconsistent. The study systematically reviewed and assessed the efficacy of melatonin in preventing AKI. Methods : A systematic literature search was conducted in the PubMed, Embase, and Cochranelibrary on May 19, 2023. Eligible records were screened according to the inclusion and exclusion criteria. The risk ratio and the corresponding 95% confidence intervals were selected to evaluate the effects of melatonin on AKI. We pooled extracted data using a fixed- or random effects model based on a heterogeneity test. Results : Six randomized controlled trials regarding the use of melatonin in preventing kidney injury met our inclusion criteria. The pooled results showed that melatonin increased the estimated glomerular filtration rate, and effectively inhibited the occurrence of AKI. Melatonin tended to reduce the serum creatinine and urea nitrogen levels, but there was no statistical significance. Conclusions : Melatonin can increase the estimated glomerular filtration rate and effectively inhibit the occurrence of AKI. More well-designed randomized controlled trials are needed to verify the protective effect of melatonin in the future.
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Affiliation(s)
- Jing Yue
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Xin Bao
- Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ling-Fei Meng
- Department of Nephrology, Second Hospital, Jilin University, Changchun, China
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21
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Ma K, Luo L, Yang M, Meng Y. The suppression of sepsis-induced kidney injury via the knockout of T lymphocytes. Heliyon 2024; 10:e23311. [PMID: 38283245 PMCID: PMC10818183 DOI: 10.1016/j.heliyon.2023.e23311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 11/23/2023] [Accepted: 11/30/2023] [Indexed: 01/30/2024] Open
Abstract
Patients with sepsis always have a high mortality rate, and acute kidney injury (AKI) is the main cause of death. It seems obvious that the immune response is involved in this process, but the specific mechanism is unknown, especially the pathogenic role of T cells and B cells needs to be further clarified. Acute kidney injury models induced by lipopolysaccharide were established using T-cell, B-cell, and T&B cell knockout mice to elucidate the role of immune cells in sepsis. Flow cytometry was used to validate the mouse models, and the pathology can confirm renal tubular injury. LPS-induced sepsis caused significant renal pathological damage, Second-generation gene sequencing showed T cells-associated pathway was enriched in sepsis. The renal tubular injury was significantly reduced in T cell and T&B cell knockout mice (BALB/c-nu, Rag1-/-), especially in BALB/c-nu mice, with a decrease in the secretion of inflammatory cytokines in the renal tissue after LPS injection. LPS injection did not produce the same effect after the knockout of B cells. We found that blocking T cells could alleviate inflammation and renal injury caused by sepsis, providing a promising strategy for controlling renal injury.
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Affiliation(s)
- Ke Ma
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Liang Luo
- The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University), Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Meixiang Yang
- The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University), Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
- The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, 517000, China
| | - Yu Meng
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
- Department of Nephrology, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Heyuan, 517000, China
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22
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Kanazashi Y, Maejima K, Johnson TA, Sasagawa S, Jikuya R, Hasumi H, Matsumoto N, Maekawa S, Obara W, Nakagawa H. Mitochondrial DNA Variants at Low-Level Heteroplasmy and Decreased Copy Numbers in Chronic Kidney Disease (CKD) Tissues with Kidney Cancer. Int J Mol Sci 2023; 24:17212. [PMID: 38139039 PMCID: PMC10743237 DOI: 10.3390/ijms242417212] [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: 09/13/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
The human mitochondrial genome (mtDNA) is a circular DNA molecule with a length of 16.6 kb, which contains a total of 37 genes. Somatic mtDNA mutations accumulate with age and environmental exposure, and some types of mtDNA variants may play a role in carcinogenesis. Recent studies observed mtDNA variants not only in kidney tumors but also in adjacent kidney tissues, and mtDNA dysfunction results in kidney injury, including chronic kidney disease (CKD). To investigate whether a relationship exists between heteroplasmic mtDNA variants and kidney function, we performed ultra-deep sequencing (30,000×) based on long-range PCR of DNA from 77 non-tumor kidney tissues of kidney cancer patients with CKD (stages G1 to G5). In total, this analysis detected 697 single-nucleotide variants (SNVs) and 504 indels as heteroplasmic (0.5% ≤ variant allele frequency (VAF) < 95%), and the total number of detected SNVs/indels did not differ between CKD stages. However, the number of deleterious low-level heteroplasmic variants (pathogenic missense, nonsense, frameshift and tRNA) significantly increased with CKD progression (p < 0.01). In addition, mtDNA copy numbers (mtDNA-CNs) decreased with CKD progression (p < 0.001). This study demonstrates that mtDNA damage, which affects mitochondrial genes, may be involved in reductions in mitochondrial mass and associated with CKD progression and kidney dysfunction.
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Affiliation(s)
- Yuki Kanazashi
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; (Y.K.); (K.M.); (T.A.J.); (S.S.)
- Department of Human Genetics, Yokohama City University, Yokohama 236-0004, Japan;
| | - Kazuhiro Maejima
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; (Y.K.); (K.M.); (T.A.J.); (S.S.)
| | - Todd A. Johnson
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; (Y.K.); (K.M.); (T.A.J.); (S.S.)
| | - Shota Sasagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; (Y.K.); (K.M.); (T.A.J.); (S.S.)
| | - Ryosuke Jikuya
- Department of Urology, Yokohama City University, Yokohama 236-0004, Japan; (R.J.); (H.H.)
| | - Hisashi Hasumi
- Department of Urology, Yokohama City University, Yokohama 236-0004, Japan; (R.J.); (H.H.)
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University, Yokohama 236-0004, Japan;
| | - Shigekatsu Maekawa
- Department of Urology, Iwate Medical University, Iwate 028-3694, Japan; (S.M.); (W.O.)
| | - Wataru Obara
- Department of Urology, Iwate Medical University, Iwate 028-3694, Japan; (S.M.); (W.O.)
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; (Y.K.); (K.M.); (T.A.J.); (S.S.)
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23
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Guerrero-Mauvecin J, Villar-Gómez N, Rayego-Mateos S, Ramos AM, Ruiz-Ortega M, Ortiz A, Sanz AB. Regulated necrosis role in inflammation and repair in acute kidney injury. Front Immunol 2023; 14:1324996. [PMID: 38077379 PMCID: PMC10704359 DOI: 10.3389/fimmu.2023.1324996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 11/08/2023] [Indexed: 12/18/2023] Open
Abstract
Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition. Regulated necrosis has recently emerged as key player in kidney injury. Specifically, there is functional evidence for a role of necroptosis, ferroptosis or pyroptosis in AKI and the AKI-to-CKD progression. Regulated necrosis may be proinflammatory and immunogenic, triggering subsequent waves of regulated necrosis. In a paradigmatic murine nephrotoxic AKI model, a first wave of ferroptosis was followed by recruitment of inflammatory cytokines such as TWEAK that, in turn, triggered a secondary wave of necroptosis which led to persistent kidney injury and decreased kidney function. A correct understanding of the specific forms of regulated necrosis, their timing and intracellular molecular pathways may help design novel therapeutic strategies to prevent or treat AKI at different stages of the condition, thus improving patient survival and the AKI-to-CKD transition. We now review key regulated necrosis pathways and their role in AKI and the AKI-to-CKD transition both at the time of the initial insult and during the repair phase following AKI.
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Affiliation(s)
- Juan Guerrero-Mauvecin
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz (IIS-FJD), Universidad Autonoma de Madrid, Madrid, Spain
| | - Natalia Villar-Gómez
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz (IIS-FJD), Universidad Autonoma de Madrid, Madrid, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
| | - Sandra Rayego-Mateos
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
- Cellular Biology in Renal Diseases Laboratory, IIS-FJD-Universidad Autónoma, Madrid, Spain
| | - Adrian M. Ramos
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz (IIS-FJD), Universidad Autonoma de Madrid, Madrid, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
| | - Marta Ruiz-Ortega
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
- Cellular Biology in Renal Diseases Laboratory, IIS-FJD-Universidad Autónoma, Madrid, Spain
- Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
| | - Alberto Ortiz
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz (IIS-FJD), Universidad Autonoma de Madrid, Madrid, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
- Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
- Instituto Reina Sofia en Investigación en Nefrología (IRSIN), Madrid, Spain
| | - Ana B. Sanz
- Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jimenez Diaz (IIS-FJD), Universidad Autonoma de Madrid, Madrid, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040), Madrid, Spain
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24
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Liu C, Liu X, He Z, Zhang J, Tan X, Yang W, Zhang Y, Yu T, Liao S, Dai L, Xu Z, Li F, Huang Y, Zhao J. Proenkephalin-A secreted by renal proximal tubules functions as a brake in kidney regeneration. Nat Commun 2023; 14:7167. [PMID: 37935684 PMCID: PMC10630464 DOI: 10.1038/s41467-023-42929-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 10/26/2023] [Indexed: 11/09/2023] Open
Abstract
Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.
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Affiliation(s)
- Chi Liu
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China.
| | - Xiaoliang Liu
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Zhongwei He
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Jiangping Zhang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Xiaoqin Tan
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Wenmin Yang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Yunfeng Zhang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Ting Yu
- Department of Respiratory Medicine, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Shuyi Liao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Lu Dai
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Zhi Xu
- Department of Respiratory Medicine, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Furong Li
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China
| | - Yinghui Huang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China.
| | - Jinghong Zhao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), 400037, Chongqing, P.R. China.
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25
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Li X, Zhong Y, Yue R, Xie J, Zhang Y, Lin Y, Li H, Xu Y, Zheng D. Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization. J Cell Mol Med 2023; 27:2876-2889. [PMID: 37471571 PMCID: PMC10538271 DOI: 10.1111/jcmm.17848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/29/2023] [Accepted: 07/05/2023] [Indexed: 07/22/2023] Open
Abstract
Acute kidney injury (AKI), mainly caused by Ischemia/reperfusion injury (IRI), is a common and severe life-threatening disease with high mortality. Accumulating evidence suggested a direct relationship between endoplasmic reticulum (ER) stress response and AKI progression. However, the role of the transmissible ER stress response, a new modulator of cell-to-cell communication, in influencing intercellular communication between renal tubular epithelial cells (TECs) and macrophages in the AKI microenvironment remains to be determined. To address this issue, we first demonstrate that TECs undergoing ER stress are able to transmit ER stress to macrophages via exosomes, promoting macrophage polarization towards the pro-inflammatory M1 phenotype in vitro and in vivo. Besides, the miR-106b-5p/ATL3 signalling axis plays a pivotal role in the transmission of ER stress in the intercellular crosstalk between TECs and macrophages. We observed an apparent increase in the expression of miR-106b-5p in ER-stressed TECs. Furthermore, we confirmed that ALT3 is a potential target protein of miR-106b-5p. Notably, the inhibition of miR-106b-5p expression in macrophages not only restores ATL3 protein level but also decreases transmissible ER stress and hinders M1 polarization, thus alleviating AKI progression. Additionally, our results suggest that the level of exosomal miR-106b-5p in urine is closely correlated with the severity of AKI patients. Taken together, our study sheds new light on the crucial role of transmissible ER stress in the treatment of AKI through the regulation of the miR-106b-5p/ATL3 axis, offering new ideas for treating AKI.
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Affiliation(s)
- Xiang Li
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
- Department of Clinical LaboratoryThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Yanan Zhong
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Rui Yue
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Juan Xie
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Yiyuan Zhang
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Yongtao Lin
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
- School of Nursing and MidwiferyJiangsu College of NursingHuai'anChina
| | - Hailun Li
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Yong Xu
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
| | - Donghui Zheng
- Department of NephrologyThe Affiliated Huai'an Hospital of Xuzhou Medical University and Huai'an Second People's HospitalHuai'anChina
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26
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Schmalkuche K, Schwinzer R, Wenzel N, Valdivia E, Petersen B, Blasczyk R, Figueiredo C. Downregulation of Swine Leukocyte Antigen Expression Decreases the Strength of Xenogeneic Immune Responses towards Renal Proximal Tubular Epithelial Cells. Int J Mol Sci 2023; 24:12711. [PMID: 37628892 PMCID: PMC10454945 DOI: 10.3390/ijms241612711] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Xenotransplantation reemerged as a promising alternative to conventional transplantation enlarging the available organ pool. However, success of xenotransplantation depends on the design and selection of specific genetic modifications and on the development of robust assays allowing for a precise assessment of tissue-specific immune responses. Nevertheless, cell-based assays are often compromised by low proliferative capacity of primary cells. Proximal tubular epithelial cells (PTECs) play a crucial role in kidney function. Here, we generated immortalized PTECs (imPTECs) by overexpression of simian virus 40 T large antigen. ImPTECs not only showed typical morphology and phenotype, but, in contrast to primary PTECs, they maintained steady cell cycling rates and functionality. Furthermore, swine leukocyte antigen (SLA) class I and class II transcript levels were reduced by up to 85% after transduction with lentiviral vectors encoding for short hairpin RNAs targeting β2-microglobulin and the class II transactivator. This contributed to reducing xenogeneic T-cell cytotoxicity (p < 0.01) and decreasing secretion of pro-inflammatory cytokines such as IL-6 and IFN-γ. This study showed the feasibility of generating highly proliferative PTECs and the development of tissue-specific immunomonitoring assays. Silencing SLA expression on PTECs was demonstrated to be an effective strategy to prevent xenogeneic cellular immune responses and may strongly support graft survival after xenotransplantation.
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Affiliation(s)
- Katharina Schmalkuche
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Reinhard Schwinzer
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transplantation Laboratory, Clinic for General, Visceral and Transplantation-Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Nadine Wenzel
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Emilio Valdivia
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Björn Petersen
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Institute of Farm Animal Genetics, Höltystr. 10, 31535 Neustadt am Rübenberge, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
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27
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DiKun KM, Gudas LJ. Vitamin A and retinoid signaling in the kidneys. Pharmacol Ther 2023; 248:108481. [PMID: 37331524 PMCID: PMC10528136 DOI: 10.1016/j.pharmthera.2023.108481] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/18/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries. VA is stored in the liver and converted to active metabolites, most notably retinoic acid (RA), which acts as an agonist for the retinoic acid receptors ((RARs α, β, and γ) to regulate gene transcription. In this review we discuss some of the actions of retinoids in the kidney after injury. For example, in an ischemia-reperfusion model in mice, injury-associated loss of proximal tubule (PT) differentiation markers occurs, followed by re-expression of these differentiation markers during PT repair. Notably, healthy proximal tubules express ALDH1a2, the enzyme that metabolizes retinaldehyde to RA, but transiently lose ALDH1a2 expression after injury, while nearby myofibroblasts transiently acquire RA-producing capabilities after injury. These results indicate that RA is important for renal tubular injury repair and that compensatory mechanisms exist for the generation of endogenous RA by other cell types upon proximal tubule injury. ALDH1a2 levels also increase in podocytes, epithelial cells of the glomeruli, after injury, and RA promotes podocyte differentiation. We also review the ability of exogenous, pharmacological doses of RA and receptor selective retinoids to treat numerous kidney diseases, including kidney cancer and diabetic kidney disease, and the emerging genetic evidence for the importance of retinoids and their receptors in maintaining or restoring kidney function after injury. In general, RA has a protective effect on the kidney after various types of injuries (eg. ischemia, cytotoxic actions of chemicals, hyperglycemia related to diabetes). As more research into the actions of each of the three RARs in the kidney is carried out, a greater understanding of the actions of vitamin A is likely to lead to new insights into the pathology of kidney disorders and the development of new therapies for kidney diseases.
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Affiliation(s)
- Krysta M DiKun
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA; New York Presbyterian Hospital, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Lorraine J Gudas
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA; Department of Urology, Weill Cornell Medicine, New York, NY, USA; New York Presbyterian Hospital, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
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Chou LF, Yang HY, Hung CC, Tian YC, Hsu SH, Yang CW. Leptospirosis kidney disease: Evolution from acute to chronic kidney disease. Biomed J 2023; 46:100595. [PMID: 37142093 PMCID: PMC10345244 DOI: 10.1016/j.bj.2023.100595] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 05/06/2023] Open
Abstract
Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.
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Affiliation(s)
- Li-Fang Chou
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; Graduate Institute of Biomedical Sciences, Department of Microbiology and Immunology, Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan
| | - Huang-Yu Yang
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chieh Hung
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ya-Chung Tian
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shen-Hsing Hsu
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan
| | - Chih-Wei Yang
- Kidney Research Center, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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29
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Previtali P, Pagani L, Risca G, Capitoli G, Bossi E, Oliveira G, Piga I, Radice A, Trezzi B, Sinico RA, Magni F, Chinello C. Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach. Int J Mol Sci 2023; 24:11756. [PMID: 37511514 PMCID: PMC10380405 DOI: 10.3390/ijms241411756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/30/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients.
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Affiliation(s)
- Paolo Previtali
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Lisa Pagani
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Giulia Risca
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre-B4, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Giulia Capitoli
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre-B4, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Eleonora Bossi
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Glenda Oliveira
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Isabella Piga
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Antonella Radice
- Microbiology Institute, ASST (Azienda Socio Sanitaria Territoriale) Santi Paolo e Carlo, 20142 Milan, Italy
| | - Barbara Trezzi
- Department of Medicine and Surgery, University of Milano Bicocca and Nephrology, 20900 Monza, Italy
- Dialysis Unit, ASST-Monza, Ospedale San Gerardo, 20900 Monza, Italy
| | - Renato Alberto Sinico
- Department of Medicine and Surgery, University of Milano Bicocca and Nephrology, 20900 Monza, Italy
- Dialysis Unit, ASST-Monza, Ospedale San Gerardo, 20900 Monza, Italy
| | - Fulvio Magni
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
| | - Clizia Chinello
- Proteomics and Metabolomics Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy
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Abdelmageed MM, Kefaloyianni E, Arthanarisami A, Komaru Y, Atkinson JJ, Herrlich A. TNF or EGFR inhibition equally block AKI-to-CKD transition: opportunities for etanercept treatment. Nephrol Dial Transplant 2023; 38:1139-1150. [PMID: 36269313 PMCID: PMC10157768 DOI: 10.1093/ndt/gfac290] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Inflammation is a key driver of the transition of acute kidney injury to progressive fibrosis and chronic kidney disease (AKI-to-CKD transition). Blocking a-disintegrin-and-metalloprotease-17 (ADAM17)-dependent ectodomain shedding, in particular of epidermal growth factor receptor (EGFR) ligands and of the type 1 inflammatory cytokine tumor necrosis factor (TNF), reduces pro-inflammatory and pro-fibrotic responses after ischemic AKI or unilateral ureteral obstruction (UUO), a classical fibrosis model. Metalloprotease or EGFR inhibition show significant undesirable side effects in humans. In retrospective studies anti-TNF biologics reduce the incidence and progression of CKD in humans. Whether TNF has a role in AKI-to-CKD transition and how TNF inhibition compares to EGFR inhibition is largely unknown. METHODS Mice were subjected to bilateral renal ischemia-reperfusion injury or unilateral ureteral obstruction. Kidneys were analyzed by histology, immunohistochemistry, qPCR, western blot, mass cytometry, scRNA sequencing, and cytokine profiling. RESULTS Here we show that TNF or EGFR inhibition reduce AKI-to-CKD transition and fibrosis equally by about 25%, while combination has no additional effect. EGFR inhibition reduced kidney TNF expression by about 50% largely by reducing accumulation of TNF expressing immune cells in the kidney early after AKI, while TNF inhibition did not affect EGFR activation or immune cell accumulation. Using scRNAseq data we show that TNF is predominantly expressed by immune cells in AKI but not in proximal tubule cells (PTC), and PTC-TNF knockout did not affect AKI-to-CKD transition in UUO. Thus, the anti-inflammatory and anti-fibrotic effects of the anti-TNF biologic etanercept in AKI-to-CKD transition rely on blocking TNF that is released from immune cells recruited or accumulating in response to PTC-EGFR signals. CONCLUSION Short-term anti-TNF biologics during or after AKI could be helpful in the prevention of AKI-to-CKD transition.
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Affiliation(s)
- Mai M Abdelmageed
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Nephrology
| | - Eirini Kefaloyianni
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Nephrology
| | - Akshayakeerthi Arthanarisami
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Nephrology
| | - Yohei Komaru
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Nephrology
| | - Jeffrey J Atkinson
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Pulmonary and Critical Care Medicine
| | - Andreas Herrlich
- Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA
- Division of Nephrology
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31
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Yang G, Tan L, Yao H, Xiong Z, Wu J, Huang X. Long-Term Effects of Severe Burns on the Kidneys: Research Advances and Potential Therapeutic Approaches. J Inflamm Res 2023; 16:1905-1921. [PMID: 37152866 PMCID: PMC10162109 DOI: 10.2147/jir.s404983] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/14/2023] [Indexed: 05/09/2023] Open
Abstract
Burns are a seriously underestimated form of trauma that not only damage the skin system but also cause various complications, such as acute kidney injury (AKI). Recent clinical studies have shown that the proportion of chronic kidney diseases (CKD) in burn patients after discharge is significantly higher than that in the general population, but the mechanism behind this is controversial. The traditional view is that CKD is associated with hypoperfusion, AKI, sepsis, and drugs administered in the early stages of burns. However, recent studies have shown that burns can cause long-term immune dysfunction, which is a high-risk factor for CKD. This suggests that burns affect the kidneys more than previously recognized. In other words, severe burns are not only an acute injury but also a chronic disease. Neglecting to study long-term kidney function in burn patients also results in a lack of preventive and therapeutic methods being developed. Furthermore, stem cells and their exosomes have shown excellent comprehensive therapeutic properties in the prevention and treatment of CKD, making them increasingly the focus of research attention. Their engineering strategy further improved the therapeutic performance. This review will focus on the research advances in burns on the development of CKD, illustrating the possible mechanism of burn-induced CKD and introducing potential biological treatment options and their engineering strategies.
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Affiliation(s)
- Guang Yang
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
- Department of Life Sciences, Yuncheng University, Yuncheng, 044006, People’s Republic of China
| | - Lishan Tan
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
| | - Hua Yao
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical College, Guilin, 541004, People’s Republic of China
| | - Zuying Xiong
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
| | - Jun Wu
- Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China
- Human Histology & Embryology Section, Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, Verona, Venetia, 37134, Italy
| | - Xiaoyan Huang
- Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China
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González-Soria I, Soto-Valadez AD, Martínez-Rojas MA, Ortega-Trejo JA, Pérez-Villalva R, Gamba G, Sánchez-Navarro A, Bobadilla NA. SerpinA3K Deficiency Reduces Oxidative Stress in Acute Kidney Injury. Int J Mol Sci 2023; 24:ijms24097815. [PMID: 37175519 PMCID: PMC10177890 DOI: 10.3390/ijms24097815] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
We previously showed that SerpinA3K is present in urine from rats and humans with acute kidney injury (AKI) and chronic kidney disease (CKD). However, the specific role of SerpinA3K during renal pathophysiology is unknown. To begin to understand the role of SerpinA3K on AKI, SerpinA3K-deficient (KOSA3) mice were studied 24 h after inducing ischemia/reperfusion (I/R) and compared to wild type (WT) mice. Four groups were studied: WT+S, WT+IR, KOSA3+S, and KOSA3+IR. As expected, I/R increased serum creatinine and BUN, with a GFR reduction in both genotypes; however, renal dysfunction was ameliorated in the KOSA3+IR group. Interestingly, the increase in UH2O2 induced by I/R was not equally seen in the KOSA3+IR group, an effect that was associated with the preservation of antioxidant enzymes' mRNA levels. Additionally, FOXO3 expression was initially greater in the KOSA3 than in the WT group. Moreover, the increase in BAX protein level and the decrease in Hif1a and Vegfa induced by I/R were not observed in the KOSA3+IR group, suggesting that these animals have better cellular responses to hypoxic injury. Our findings suggest that SerpinA3K is involved in the renal oxidant response, HIF1α/VEGF pathway, and cell apoptosis.
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Affiliation(s)
- Isaac González-Soria
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
- PECEM (MD/PhD), Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Axel D Soto-Valadez
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Miguel Angel Martínez-Rojas
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Juan Antonio Ortega-Trejo
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Rosalba Pérez-Villalva
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Andrea Sánchez-Navarro
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Norma A Bobadilla
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Martinelli RP, Rayego-Mateos S, Alique M, Márquez-Expósito L, Tejedor-Santamaria L, Ortiz A, González-Parra E, Ruiz-Ortega M. Vitamin D, Cellular Senescence and Chronic Kidney Diseases: What Is Missing in the Equation? Nutrients 2023; 15:1349. [PMID: 36986078 PMCID: PMC10056834 DOI: 10.3390/nu15061349] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/12/2023] Open
Abstract
As life expectancy increases in many countries, the prevalence of age-related diseases also rises. Among these conditions, chronic kidney disease is predicted to become the second cause of death in some countries before the end of the century. An important problem with kidney diseases is the lack of biomarkers to detect early damage or to predict the progression to renal failure. In addition, current treatments only retard kidney disease progression, and better tools are needed. Preclinical research has shown the involvement of the activation of cellular senescence-related mechanisms in natural aging and kidney injury. Intensive research is searching for novel treatments for kidney diseases as well as for anti-aging therapies. In this sense, many experimental shreds of evidence support that treatment with vitamin D or its analogs can exert pleiotropic protective effects in kidney injury. Moreover, vitamin D deficiency has been described in patients with kidney diseases. Here, we review recent evidence about the relationship between vitamin D and kidney diseases, explaining the underlying mechanisms of the effect of vitamin D actions, with particular attention to the modulation of cellular senescence mechanisms.
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Affiliation(s)
- Romina P. Martinelli
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma, 28040 Madrid, Spain
| | - Sandra Rayego-Mateos
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma, 28040 Madrid, Spain
- Ricors2040, 28029 Madrid, Spain
| | - Matilde Alique
- Ricors2040, 28029 Madrid, Spain
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
| | - Laura Márquez-Expósito
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma, 28040 Madrid, Spain
- Ricors2040, 28029 Madrid, Spain
| | - Lucia Tejedor-Santamaria
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma, 28040 Madrid, Spain
- Ricors2040, 28029 Madrid, Spain
| | - Alberto Ortiz
- Ricors2040, 28029 Madrid, Spain
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Emilio González-Parra
- Ricors2040, 28029 Madrid, Spain
- Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma, 28040 Madrid, Spain
- Ricors2040, 28029 Madrid, Spain
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Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, Mora-Fernández C, Marchant V, Donate-Correa J, Navarro-González JF, Ortiz A, Ruiz-Ortega M. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int 2023; 103:282-296. [PMID: 36470394 DOI: 10.1016/j.kint.2022.10.030] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 10/05/2022] [Accepted: 10/31/2022] [Indexed: 12/07/2022]
Abstract
Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016. Given the contribution of inflammation to the pathogenesis of DKD, we review the impact on kidney inflammation of the current standard of care, therapies undergoing clinical trials, or repositioned drugs for DKD. Moreover, we review recent advances in the molecular regulation of inflammation in DKD and discuss potential novel therapeutic strategies with clinical relevance. Finally, we provide a road map for future research aimed at integrating the growing knowledge on inflammation and DKD into clinical practice to foster improvement of patient outcomes.
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Affiliation(s)
- Sandra Rayego-Mateos
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain
| | - Raul R Rodrigues-Diez
- Ricord2040, Instituto de Salud Carlos II, Spain; Translational Immunology, Instituto de Investigación Sanitaria del Principado de Asturias ISPA, Oviedo, Asturias, Spain
| | - Beatriz Fernandez-Fernandez
- Ricord2040, Instituto de Salud Carlos II, Spain; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma, Madrid, Spain
| | - Carmen Mora-Fernández
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Vanessa Marchant
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain
| | - Javier Donate-Correa
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F Navarro-González
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Alberto Ortiz
- Ricord2040, Instituto de Salud Carlos II, Spain; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma, Madrid, Spain
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain.
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Metabolomic Analysis of Stephania tetrandra- Astragalus membranaceus Herbal Pair-Improving Nephrotic Syndrome Identifies Activation of IL-13/STAT6 Signaling Pathway. Pharmaceuticals (Basel) 2023; 16:ph16010088. [PMID: 36678585 PMCID: PMC9863900 DOI: 10.3390/ph16010088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
The Stephania tetrandra−Astragalus membranaceus herbal pair (FH) is a classic herbal pair widely used in the treatment of nephrotic syndrome (NS). The effects of Stephania tetrandra (FJ) and Astragalus membranaceus (HQ) on NS have been reported, but the mechanism of their combination on the improvement of NS are still unclear. The NS model was established by injecting adriamycin into the tail vein. FH intervention reduced the levels of serum triglyceride, total cholesterol, interleukin-6 (IL-6), blood urea nitrogen (BUN), urinary protein, and the gene expression levels of aquaporin 2 (AQP2) and arginine vasopressin (AVP) in NS rats. In addition, FH improved kidney injury in NS rats by inhibiting the expression of interleukin 13 (IL-13), phospho-signal transducers, and activators of transcription 6 (p-STAT6), Bax, cleaved-caspase3, while promoting the expression of Bcl-2. By comprehensive comparison of multiple indexes, the effects of FH on lipid metabolism, glomerular filtration rate, and inflammation were superior to that of FJ and HQ. Metabonomic studies showed that, compared with FJ and HQ, FH intervention significantly regulated tricarboxylic acid (TCA) cycle, cysteine and methionine metabolism, and alanine, aspartic acid and glutamic acid metabolism. Pearson correlation analysis showed that succinic acid and L-aspartic acid were negatively correlated with urinary protein, cystatin C (Cys C) and BUN (p < 0.05). In summary, FH could reduce renal injury and improve NS through inhibiting the IL-13/STAT6 signal pathway, regulating endogenous metabolic pathways, such as TCA cycle, and inhibiting the expression of AQP2 and AVP genes. This study provides a comprehensive strategy to reveal the mechanism of FH on the treatment of NS, and also provides a reasonable way to clarify the compatibility of traditional Chinese medicine.
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Li J, Gong X. Bibliometric and visualization analysis of kidney repair associated with acute kidney injury from 2002 to 2022. Front Pharmacol 2023; 14:1101036. [PMID: 37153766 PMCID: PMC10157647 DOI: 10.3389/fphar.2023.1101036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
Background: Renal repair is closely related to the prognosis of acute kidney injury (AKI) and has attracted increasing attention in the research field. However, there is a lack of a comprehensive bibliometric analysis in this research area. This study aims at exploring the current status and hotspots of renal repair research in AKI from the perspective of bibliometrics. Methods: Studies published between 2002 and 2022 related to kidney repair after AKI were collected from Web of Science core collection (WoSCC) database. Bibliometric measurement and knowledge graph analysis to predict the latest research trends in the field were performed using bibliometrics software CiteSpace and VOSviewer. Results: The number of documents related to kidney repair after AKI has steadily increased over 20 years. The United States and China contribute more than 60% of documents and are the main drivers of research in this field. Harvard University is the most active academic institution that contributes the most documents. Humphreys BD and Bonventre JV are the most prolific authors and co-cited authors in the field. The American Journal of Physiology-Renal Physiology and Journal of the American Society of Nephrology are the most popular journals in the field with the greatest number of documents. "exosome", "macrophage polarization", "fibroblast", and" aki-ckd transition" are high-frequency keywords in this field in recent years. Extracellular vesicles (including exosomes), macrophage polarization, cell cycle arrest, hippo pathway, and sox9 are current research hotspots and potential targets in this field. Conclusion: This is the first comprehensive bibliometric study on the knowledge structure and development trend of AKI-related renal repair research in recent years. The results of the study comprehensively summarize and identify research frontiers in AKI-related renal repair.
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Ciarambino T, Crispino P, Giordano M. Gender and Renal Insufficiency: Opportunities for Their Therapeutic Management? Cells 2022; 11:cells11233820. [PMID: 36497080 PMCID: PMC9740491 DOI: 10.3390/cells11233820] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 11/30/2022] Open
Abstract
Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies.
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Affiliation(s)
- Tiziana Ciarambino
- Internal Medicine Department, Hospital of Marcianise, ASL Caserta, 81031 Caserta, Italy
- Correspondence: (T.C.); (M.G.)
| | - Pietro Crispino
- Emergency Department, Hospital of Latina, ASL Latina, 04100 Latina, Italy
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Science, University of Campania, Luigi Vanvitelli, 80138 Naples, Italy
- Correspondence: (T.C.); (M.G.)
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McCullough KR, Akhter J, Taheri MJ, Traylor A, Zmijewska AA, Verma V, Hudson MC, Sachdeva A, Erman EN, Moore KH, George JF, Bolisetty S. Functional consequence of myeloid ferritin heavy chain on acute and chronic effects of rhabdomyolysis-induced kidney injury. Front Med (Lausanne) 2022; 9:894521. [PMID: 36160140 PMCID: PMC9492979 DOI: 10.3389/fmed.2022.894521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Acute kidney injury (AKI) is a serious complication of rhabdomyolysis that significantly impacts survival. Myoglobin released from the damaged muscle accumulates in the kidney, causing heme iron-mediated oxidative stress, tubular cell death, and inflammation. In response to injury, myeloid cells, specifically neutrophils and macrophages, infiltrate the kidneys, and mediate response to injury. Ferritin, comprised of ferritin light chain and ferritin heavy chain (FtH), is vital for intracellular iron handling. Given the dominant role of macrophages and heme-iron burden in the pathogenesis of rhabdomyolysis, we studied the functional role of myeloid FtH in rhabdomyolysis-induced AKI and subsequent fibrosis. Using two models of rhabdomyolysis induced AKI, we found that during the acute phase, myeloid FtH deletion did not impact rhabdomyolysis-induced kidney injury, cell death or cell proliferation, suggesting that tubular heme burden is the dominant injury mechanism. We also determined that, while the kidney architecture was markedly improved after 28 days, tubular casts persisted in the kidneys, suggesting sustained damage or incomplete recovery. We further showed that rhabdomyolysis resulted in an abundance of disparate intra-renal immune cell populations, such that myeloid populations dominated during the acute phase and lymphoid populations dominated in the chronic phase. Fibrotic remodeling was induced in both genotypes at 7 days post-injury but continued to progress only in wild-type mice. This was accompanied by an increase in expression of pro-fibrogenic and immunomodulatory proteins, such as transforming growth factor-β, S100A8, and tumor necrosis factor-α. Taken together, we found that while the initial injury response to heme burden was similar, myeloid FtH deficiency was associated with lesser interstitial fibrosis. Future studies are warranted to determine whether this differential fibrotic remodeling will render these animals more susceptible to a second AKI insult or progress to chronic kidney disease at an accelerated pace.
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Affiliation(s)
- Kayla R. McCullough
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Juheb Akhter
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mauhaun J. Taheri
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Amie Traylor
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Anna A. Zmijewska
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Vivek Verma
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Matthew C. Hudson
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Abhishek Sachdeva
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Elise N. Erman
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kyle H. Moore
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - James F. George
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Subhashini Bolisetty
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
- *Correspondence: Subhashini Bolisetty,
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