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Agrawal N, Afzal M, Almalki WH, Ballal S, Sharma GC, Krithiga T, Panigrahi R, Saini S, Ali H, Goyal K, Rana M, Abida Khan. Longevity mechanisms in cardiac aging: exploring calcium dysregulation and senescence. Biogerontology 2025; 26:94. [PMID: 40259024 DOI: 10.1007/s10522-025-10229-8] [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: 02/16/2025] [Accepted: 03/20/2025] [Indexed: 04/23/2025]
Abstract
Cardiac aging is a multistep process that results in a loss of various structural and functional heart abilities, increasing the risk of heart disease. Since its remarkable discovery in the early 1800s, when limestone is heated, calcium's importance has been defined in numerous ways. It can help stiffen shells and bones, function as a reducing agent in chemical reactions, and play a central role in cellular signalling. The movement of calcium ions in and out of cells and between those is referred to as calcium signalling. It influences the binding of the ligand, enzyme activity, electrochemical gradients, and other cellular processes. Calcium signalling is critical for both contraction and relaxation under the sliding filament model of heart muscle. However, with age, the heart undergoes changes that lead to increases in cardiac dysfunction, such as myocardial fibrosis, decreased cardiomyocyte function, and noxious disturbances in calcium homeostasis. Additionally, when cardiac tissues age, cellular senescence, a state of irreversible cell cycle arrest, accumulates and begins to exacerbate tissue inflammation and fibrosis. This review explores the most recent discoveries regarding the role of senescent cell accumulation and calcium signalling perturbances in cardiac aging. Additionally, new treatment strategies are used to reduce aged-related heart dysfunction by targeting senescent cells and modulating calcium homeostasis.
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Affiliation(s)
- Neetu Agrawal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Girish Chandra Sharma
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - T Krithiga
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rajashree Panigrahi
- Department of Microbiology IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Abida Khan
- Center For Health Research, Northern Border University, Arar 73213, Saudi Arabia
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Li X, Zhu D, Zhao B, Li Q, Jin P. Alternative splicing: Therapeutic target for vasculopathy in diabetic complications. Life Sci 2025; 362:123331. [PMID: 39734014 DOI: 10.1016/j.lfs.2024.123331] [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: 08/25/2024] [Revised: 12/03/2024] [Accepted: 12/19/2024] [Indexed: 12/31/2024]
Abstract
It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.
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Affiliation(s)
- Xiaoyue Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Dong Zhu
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Bingkun Zhao
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Peisheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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Xu P, Jiang M, Chen J, Zhou Y, Wang Z. The Long-Range Chromosomal Interaction Controlling Klotho Gene Expression in Human Chronic Kidney Disease. ACS OMEGA 2024; 9:51264-51270. [PMID: 39758635 PMCID: PMC11696417 DOI: 10.1021/acsomega.4c07967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/22/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025]
Abstract
Cis-regulatory elements bridge enhancers and gene promoters to control gene expression via distal DNA interaction and three-dimensional chromosomal conformation organization. The aberrant changes of cis-acting regulatory systems as one type of the epigenetic regulative ways may be connected with human genetic diseases. Klotho, as an antiaging protein, is selectively expressed in kidney tissues and plays a crucial role in preventing chronic kidney disease (CKD) and renal fibrosis. However, the underlying transcription regulatory mechanism of Klotho in CKD is not fully understood. Herein, we analyzed the spatial organization of the chromatin region spanning 2 Mb upstream Klotho in human renal punctured CKD tissues using chromosome conformation capture (3C)-qPCR and identified the distal interaction of the Klotho promoter with certain specific chromatin regions characterized as the regulatory elements. Moreover, we determined that four DNase I hypersensitive sites (DHSs) involved in the regulation of Klotho gene expression lost their activities in CKD tissues compared to control accompanied by the reduction of H3K27ac. Finally, the CCCTC-binding factor (CTCF) sites were validated on the DHSs beyond the Klotho promoter by chromatin looping formation through the recruitment of CTCF.
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Affiliation(s)
- Pengwei Xu
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Minjun Jiang
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Jianchun Chen
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Yongqiang Zhou
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
| | - Zhenfan Wang
- Department of Urology, Suzhou Ninth Hospital affiliated to Soochow University, Suzhou 215000, China
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Zaimi M, Grapsa E. Current therapeutic approach of chronic kidney disease-mineral and bone disorder. Ther Apher Dial 2024; 28:671-689. [PMID: 38898685 DOI: 10.1111/1744-9987.14177] [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: 02/29/2024] [Revised: 05/14/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024]
Abstract
Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD-mineral and bone disorder (CKD-MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD-MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD-MBD, anti-osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD-MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD-MBD based on the current literature with special attention to recent advances.
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Affiliation(s)
- Maria Zaimi
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
| | - Eirini Grapsa
- National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
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Harrison‐Bernard LM, Raij L, Tian RX, Jaimes EA. Genetically conditioned interaction among microRNA-155, alpha-klotho, and intra-renal RAS in male rats: Link to CKD progression. Physiol Rep 2024; 12:e16172. [PMID: 39375174 PMCID: PMC11458328 DOI: 10.14814/phy2.16172] [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: 08/22/2023] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 10/09/2024] Open
Abstract
Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit.
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Affiliation(s)
- L. M. Harrison‐Bernard
- Department of PhysiologyLouisiana State University Health Sciences CenterNew OrleansLouisianaUSA
| | - L. Raij
- Katz Family Division of NephrologyUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - R. X. Tian
- South Florida Veterans Administration FoundationMiamiFloridaUSA
| | - E. A. Jaimes
- Renal ServiceMemorial Sloan Kettering Cancer Center and Weill Cornell Medical CollegeNew YorkNew YorkUSA
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Jankowski J, Lee HK, Liu C, Wilflingseder J, Hennighausen L. Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b. Commun Biol 2024; 7:1142. [PMID: 39277686 PMCID: PMC11401919 DOI: 10.1038/s42003-024-06855-6] [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: 03/29/2024] [Accepted: 09/06/2024] [Indexed: 09/17/2024] Open
Abstract
Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice present normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.
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Affiliation(s)
- Jakub Jankowski
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA.
- , 8 Center Drive, Room 107, 20892, Bethesda, MD, USA.
| | - Hye Kyung Lee
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA
| | - Chengyu Liu
- Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, MD, 20892, USA
| | - Julia Wilflingseder
- Department of Physiology and Pathophysiology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Lothar Hennighausen
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA
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Prud’homme GJ, Wang Q. Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging. Cells 2024; 13:1413. [PMID: 39272986 PMCID: PMC11394293 DOI: 10.3390/cells13171413] [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: 08/01/2024] [Revised: 08/17/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.
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Affiliation(s)
- Gérald J. Prud’homme
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 220 Walmer Rd, Toronto, ON M5R 3R7, Canada
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200030, China
- Shanghai Innogen Pharmaceutical Co., Ltd., Shanghai 201318, China
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Suzuki K, Soeda K, Komaba H. Crosstalk between kidney and bone: insights from CKD-MBD. J Bone Miner Metab 2024; 42:463-469. [PMID: 39060498 DOI: 10.1007/s00774-024-01528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024]
Abstract
The kidneys play an important role in the regulation of phosphate and calcium balance and serum concentrations, coordinated by fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D). In patients with chronic kidney disease (CKD), this regulation is impaired, leading to CKD-mineral and bone disorder (CKD-MBD), characterized by decreased 1,25D, elevated FGF23, secondary hyperparathyroidism, hyperphosphatemia, bone abnormalities, and vascular and soft-tissue calcification. While bone abnormalities associated with CKD-MBD, known as renal osteodystrophy, have been recognized as the most typical interaction between the kidney and bone, a number of other kidney-bone interactions have been identified, for which our knowledge of the pathogenesis of CKD-MBD has played an important role. This article summarizes recent findings on CKD-MBD and explores the crosstalk between the kidney and bone from the perspective of CKD-MBD.
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Affiliation(s)
- Kodai Suzuki
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
- Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Keisuke Soeda
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan
| | - Hirotaka Komaba
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan.
- The Institute of Medical Sciences, Tokai University, Isehara, Japan.
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Zheng Q, Zhao J, Yuan J, Qin Y, Zhu Z, Liu J, Sun S. Delaying Renal Aging: Metformin Holds Promise as a Potential Treatment. Aging Dis 2024:AD.2024.0168. [PMID: 39012670 DOI: 10.14336/ad.2024.0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/06/2024] [Indexed: 07/17/2024] Open
Abstract
Given the rapid aging of the population, age-related diseases have become an excessive burden on global health care. The kidney, a crucial metabolic organ, ages relatively quickly. While the aging process itself does not directly cause kidney damage, the physiological changes that accompany it can impair the kidney's capacity for self-repair. This makes aging kidneys more susceptible to diseases, including increased risks of chronic kidney disease and end-stage renal disease. Therefore, delaying the progression of renal aging and preserving the youthful vitality of the kidney are crucial for preventing kidney diseases. However, effective strategies against renal aging are still lacking due to the underlying mechanisms of renal aging, which have not been fully elucidated. Accumulating evidence suggests that metformin has beneficial effects in mitigating renal aging. Metformin has shown promising anti-aging results in animal models but has not been tested for this purpose yet in clinical trials. These findings indicate the potential of metformin as an anti-renal aging drug. In this review, we primarily discuss the characteristics and mechanisms of kidney aging and the potential effects of metformin against renal aging.
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Affiliation(s)
- Qiao Zheng
- Department of Postgraduate Student, Xi'an Medical University, Xi'an, China
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jin Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinguo Yuan
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yunlong Qin
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhanxin Zhu
- Department of Postgraduate Student, Xi'an Medical University, Xi'an, China
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jie Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Qiu S, Li C, Zhu J, Guo Z. Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007-2016. Lipids Health Dis 2024; 23:188. [PMID: 38907289 PMCID: PMC11191244 DOI: 10.1186/s12944-024-02172-3] [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: 03/29/2024] [Accepted: 05/31/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it has been reported that α-Klotho is downregulated in patients with insulin resistance (IR), the association between Klotho and IR is complex and controversial. The triglyceride-glucose (TyG) index has provided a practical method for assessing IR. With this in mind, our study aimed to investigate the relationship between the TyG index and soluble α-Klotho protein levels in US populations, both with and without diabetes mellitus. METHODS This cross-sectional study analyzed data from middle-aged and older participants in the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. The participants were divided into two groups based on their diabetes mellitus status: those with diabetes and those without diabetes. To evaluate the relationship between the TyG index and the concentration of the α-Klotho protein in each group, a series of survey-weighted multivariable linear regression models were employed. Furthermore, to examine the association between these two variables, multivariable-adjusted restricted cubic spline curves and subgroup analysis were generated. RESULTS The study involved 6,439 adults aged 40 years or older, with a mean age of 57.8 ± 10.9 years. Among them, 1577 (24.5%) had diabetes mellitus. A subgroup analysis indicated that the presence of diabetes significantly affected the relationship between the TyG index and the α-Klotho level. After considering all covariables, regression analysis of the participants without diabetes revealed that the α-Klotho concentration decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) with each one unit increase in TyG (p < 0.001). The decline in α-Klotho levels with elevated TyG was more pronounced in the female population. In patients with diabetes mellitus, a non-linear association between the TyG index and α-Klotho was observed. There was no significant correlation observed between the two when TyG index were below 9.7. However, there was an increase in klotho levels of 106.44 pg/ml for each unit increase in TyG index above 9.7 (95% CI: 28.13, 184.74) (p = 0.008). CONCLUSION Our findings suggested that the presence of diabetes may influence the relationship between the TyG index and soluble α-Klotho. Furthermore, there seem to be sex differences in individuals without diabetes. Further studies are necessary to validate these findings.
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Affiliation(s)
- Shujuan Qiu
- Department of Nephrology, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Quiwen District, Weifang, 261041, Shandong, China.
| | - Chunlei Li
- Department of Nephrology, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Quiwen District, Weifang, 261041, Shandong, China
| | - Jinhua Zhu
- Zhucheng Nanhu Community Health Service Center, No. 2000, Tourism Road, South Lake Ecological Economic Development District, Zhucheng, 262200, Shandong, China
| | - Zhentao Guo
- Department of Nephrology, Affiliated Hospital of Shandong Second Medical University, No. 2428, Yuhe Road, Quiwen District, Weifang, 261041, Shandong, China
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Jankowski J, Lee HK, Liu C, Wilflingseder J, Hennighausen L. Sexually dimorphic renal expression of Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b. RESEARCH SQUARE 2024:rs.3.rs-4188774. [PMID: 38712042 PMCID: PMC11071613 DOI: 10.21203/rs.3.rs-4188774/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice presented normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.
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Affiliation(s)
- Jakub Jankowski
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Hye Kyung Lee
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Chengyu Liu
- Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, MD 20892, USA
| | - Julia Wilflingseder
- Department of Physiology and Pathophysiology, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Lothar Hennighausen
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
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Rodríguez-Ortiz ME, Jurado-Montoya D, Valdés-Díaz K, García-Sáez RM, Torralbo AI, Obrero T, Vidal-Jiménez V, Jiménez MJ, Carmona A, Guerrero F, Pendón-Ruiz de Mier MV, Rodelo-Haad C, Canalejo A, Rodríguez M, Soriano-Cabrera S, Muñoz-Castañeda JR. Cognitive Impairment Related to Chronic Kidney Disease Is Associated with a Decreased Abundance of Membrane-Bound Klotho in the Cerebral Cortex. Int J Mol Sci 2024; 25:4194. [PMID: 38673780 PMCID: PMC11050028 DOI: 10.3390/ijms25084194] [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: 02/29/2024] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.
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Affiliation(s)
- María E. Rodríguez-Ortiz
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
| | - Daniel Jurado-Montoya
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Karen Valdés-Díaz
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Raquel M. García-Sáez
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Ana I. Torralbo
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Teresa Obrero
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Victoria Vidal-Jiménez
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - María J. Jiménez
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Andrés Carmona
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - Fátima Guerrero
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
- Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain; (D.J.-M.); (K.V.-D.); (R.M.G.-S.); (T.O.); (V.V.-J.); (M.J.J.)
| | - María V. Pendón-Ruiz de Mier
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
| | - Cristian Rodelo-Haad
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
| | - Antonio Canalejo
- Department of Integrated Sciences/Research Center on Natural Resources, Health, and Environment (RENSMA), University of Huelva Campus el Carmen, Avda. Del Tres de Marzo, s/n, 21071 Huelva, Spain;
| | - Mariano Rodríguez
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
| | - Sagrario Soriano-Cabrera
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
| | - Juan R. Muñoz-Castañeda
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Avda. Menéndez Pidal, s/n, 14004 Cordoba, Spain; (M.E.R.-O.); (M.V.P.-R.d.M.); (C.R.-H.); (S.S.-C.); (J.R.M.-C.)
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Instituto de Salud Carlos III, 28029 Madrid, Spain; (A.I.T.); (A.C.); (F.G.)
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Jayaraj JM, Muthusamy K. Role of deleterious nsSNPs of klotho protein and their drug response: a computational mechanical insights. J Biomol Struct Dyn 2024; 42:2886-2896. [PMID: 37216366 DOI: 10.1080/07391102.2023.2214230] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 04/23/2023] [Indexed: 05/24/2023]
Abstract
Worldwide, the burden of chronic kidney disease (CKD) has increased rapidly and is a lethal disease. The klotho protein plays a vital role in the regulatory mechanism in the progression of CKD. Particularly the decreased expression of klothoand its genetic variations might affect the potency of drugs. This study aims to identify a new drug molecule, which works equipotential in all types of klotholike wild and mutant variants. All non-synonymous SNPs were predicted by several SNP tools. Where, two missense variants were examined as vulnerable, significantly damaging, and also involved in the structural conformational changes of the protein. Based on structure-based screening, E-pharmacophore screening, binding mode analysis, binding free energy analysis, QM/MM, and molecular dynamics analysis a lead compound (Lifechemical_F2493-2038) was identified as an effective agonistic molecule hence the identified Lifechemical_F2493-2038 compound is well bound to the wild and mutant proteins which found to increase the expression of klotho.Communicated by Ramaswamy H. Sarma.
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14
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Jankowski J, Lee HK, Liu C, Wilflingseder J, Hennighausen L. Sexually dimorphic renal expression of Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.29.582831. [PMID: 38529500 PMCID: PMC10962737 DOI: 10.1101/2024.02.29.582831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice presented normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.
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Affiliation(s)
- Jakub Jankowski
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Hye Kyung Lee
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
| | - Chengyu Liu
- Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, MD 20892, USA
| | - Julia Wilflingseder
- Department of Physiology and Pathophysiology, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Lothar Hennighausen
- Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
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15
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Mbadu Lelo S, Musungayi Kajingulu FP, Makulo JR, Mayamba Nlandu Y, Busanga Bukabau J, Koso Mbulupasu P, Luzayadio Longo A, Losa Luse JN, Momeme Mokoli V, Kiswaya Sumaili E, Mangani Nseka N. 25 [OH] Vitamin D and Intact Parathyroid Hormone in Congolese Hemodialysis Patients: Evaluation of KDIGO Targets. Int J Nephrol Renovasc Dis 2024; 17:71-79. [PMID: 38405026 PMCID: PMC10887870 DOI: 10.2147/ijnrd.s440809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 02/14/2024] [Indexed: 02/27/2024] Open
Abstract
Background Data on 25 [OH] vitamin D and intact parathyroid hormone [iPTH] in hemodialysis patients are very limited in sub-Saharan African countries. The present study aimed to assess the magnitude of hypovitaminosis D, and to evaluate the achievement of iPTH KDIGO 2017 targets among chronic hemodialysis patients followed in Kinshasa. Methods We conducted a multicenter cross-sectional study in 6 hospitals in Kinshasa. All patients followed on hemodialysis for more than 3 months were included. Hypovitaminosis D was defined as <30 ng/mL (insufficiency = 20-29 ng/mL; deficiency if <20 ng/mL) and the targets for iPTH values were based on the 2017 KDIGO guidelines. The determinants for hypovitaminosis D were evaluated by logistic regression. Results 251 patients [mean age 56 ± 14 years, 72.5% men, 63% hypertensive, 31% diabetic, 100% supplemented with native 25 [OH] vitamin D + CaCO3 were included. Hypovitaminosis D was found in 79.7% (deficiency 47.4%) and was associated with the male gender aOR 2.7 [1.4-5.2], p = 0.004, the low-permeability dialyzer 2.2 [1.1-4.2], p = 0.025 and anemia 3.9 [1.2-12.7], p = 0.022. Only 40% of patients with 25 [OH] vitamin D deficiency had iPTH according to KDIGO targets vs 6% of patients with severe hyperparathyroidism (iPTH > 600 pg/mL), 45% with levels between 16 and 150 pg/mL and 9% a iPTH ≤ 15 pg/mL. Conclusion Despite a sunny environment, a large proportion of Congolese hemodialysis patients have hypovitaminosis D, in particular a deficiency. Among them, less than half have target iPTH values. These results show the benefit of regular monitoring of these parameters in order to optimize treatment.
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Affiliation(s)
- Samuel Mbadu Lelo
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Hemodialysis Center, Ngaliema Medical Center, Kinshasa, Democratic Republic of the Congo
| | - François-Pantaléon Musungayi Kajingulu
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Dialysis Center, HJ Hospital, Kinshasa, Democratic Republic of the Congo
- Department of Internal Medicine, Saint-Joseph Hospital, Kinshasa, Democratic Republic of the Congo
| | - Jean-Robert Makulo
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Hemodialysis Center, Ngaliema Medical Center, Kinshasa, Democratic Republic of the Congo
| | - Yannick Mayamba Nlandu
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Hemodialysis Center, Centre Médical de Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Justine Busanga Bukabau
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Hemodialysis Center, Centre Médical de Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Pierre Koso Mbulupasu
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Department of Internal Medicine, Clinique Ngaliema, Kinshasa, Democratic Republic of the Congo
| | - Augustin Luzayadio Longo
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
| | - Jeanine Nina Losa Luse
- Hemodialysis Center, Hôpital Général de Référence de Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Vieux Momeme Mokoli
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
- Hemodialysis Center, Ngaliema Medical Center, Kinshasa, Democratic Republic of the Congo
| | - Ernest Kiswaya Sumaili
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
| | - Nazaire Mangani Nseka
- Hemodialysis Center, Division of Nephrology, Kinshasa University Hospital, Kinshasa, Democratic Republic of the Congo
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Zhang X, Li L, Tan H, Hong X, Yuan Q, Hou FF, Zhou L, Liu Y. Klotho-derived peptide 1 inhibits cellular senescence in the fibrotic kidney by restoring Klotho expression via posttranscriptional regulation. Theranostics 2024; 14:420-435. [PMID: 38164143 PMCID: PMC10750200 DOI: 10.7150/thno.89105] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 11/16/2023] [Indexed: 01/03/2024] Open
Abstract
Background: Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. Methods: The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. Results: KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. Conclusion: These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.
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Affiliation(s)
- Xiaoyao Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huishi Tan
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Hong
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Yuan
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Lili Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Youhua Liu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangzhou, China
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Junho CVC, Frisch J, Soppert J, Wollenhaupt J, Noels H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin Kidney J 2023; 16:1786-1803. [PMID: 37915935 PMCID: PMC10616472 DOI: 10.1093/ckj/sfad085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 11/03/2023] Open
Abstract
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
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Affiliation(s)
| | - Janina Frisch
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
| | - Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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18
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Sun F, Liang P, Wang B, Liu W. The fibroblast growth factor-Klotho axis at molecular level. Open Life Sci 2023; 18:20220655. [PMID: 37941788 PMCID: PMC10628560 DOI: 10.1515/biol-2022-0655] [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: 11/16/2022] [Revised: 06/03/2023] [Accepted: 06/10/2023] [Indexed: 11/10/2023] Open
Abstract
Klotho is a recently discovered protein that has positive effects on all systems of the body, for example, regulating calcium and phosphorus metabolism, protecting nerves, delaying aging and so on. Fibroblast growth factors (FGFs) are a group of polypeptides that function throughout the body by binding with cell surface FGF receptors (FGFRs). Endocrine FGFs require Klotho as a co-receptor for FGFRs. There is increasing evidence that Klotho participates in calcium and phosphorus regulation and metabolic regulation via the FGF-Klotho axis. Moreover, soluble Klotho can function as a separate hormone to regulate homeostasis on various ion channels and carrier channels on the cell surface. This review mainly explains the molecular basis of the membrane signaling mechanism of Klotho.
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Affiliation(s)
- Fuqiang Sun
- School of Anesthesiology, Weifang Medical University, Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, Weifang261053, Shandong, China
| | - Panpan Liang
- School of Basic Medical Sciences, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Bo Wang
- School of Anesthesiology, Weifang Medical University, Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, Weifang261053, Shandong, China
| | - Wenbo Liu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang261000, Shandong, China
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19
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Larivière R, Ung RV, Picard S, Richard DE, Mac-Way F, Agharazii M. Antihypertensive treatment with hydrochlorothiazide-hydralazine combination aggravates medial vascular calcification in CKD rats with mineral bone disorder. Front Cardiovasc Med 2023; 10:1241943. [PMID: 37840953 PMCID: PMC10570511 DOI: 10.3389/fcvm.2023.1241943] [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: 06/17/2023] [Accepted: 09/18/2023] [Indexed: 10/17/2023] Open
Abstract
Background Arterial stiffness and medial vascular calcification, leading to isolated systolic blood pressure (BP), are major cardiovascular risk factors in patients with chronic kidney disease (CKD) and mineral bone disorders (MBD). The impact of BP on MBD-induced medial vascular calcification in CKD remains uncertain. We investigated whether BP reduction improves arterial stiffness and medial vascular calcification in a rat model of CKD-MBD. Methods CKD was induced in Wistar rats by subtotal nephrectomy. Then, MBD was generated by a Ca/P-rich diet with calcitriol supplementation to induce medial vascular calcification. Two antihypertensive treatments were evaluated: (1) the angiotensin AT1 receptor antagonist losartan, and (2) the combination of the thiazide diuretic hydrochlorothiazide and the direct vasodilator hydralazine (HCTZ/HY). After 5 weeks, mean BP (MBP), pulse pressure (PP), and pulse wave velocity (PWV) were determined. Vascular calcification was assessed in the thoracic aorta. Results While MBP was similar in CKD-MBD and control CKD rats, PP and PWV were increased in CKD-MBD rats. The heightened arterial stiffness in CKD-MBD rats was associated with diffused medial calcification along the thoracic aorta. Although both losartan and HCTZ/HY reduced MBP in CKD-MBD rats, losartan did not affect PP and PWV nor medial vascular calcification, whereas HCTZ/HY, unexpectedly, further increased arterial stiffness and medial vascular calcification. Conclusion In the rat model of CKD-MBD, antihypertensive treatment with losartan did not affect arterial stiffness or medial vascular calcification. However, HCTZ/HY treatment aggravated arterial stiffness and vascular calcification despite a similar reduction of MBP, suggesting a blood pressure-independent mechanism for vascular calcification.
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Affiliation(s)
- Richard Larivière
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - Roth-Visal Ung
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
| | - Sylvain Picard
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
| | - Darren E. Richard
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
- Department of Molecular Biology, Medical Biochemistry, and Pathology, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - Fabrice Mac-Way
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - Mohsen Agharazii
- Research Centre CHU de Québec, Endocrinology and Nephrology Axis, L'Hôtel-Dieu de Québec Hospital, Université Laval, Quebec, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada
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20
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Donate-Correa J, Martín-Núñez E, Mora-Fernández C, González-Luis A, Martín-Olivera A, Navarro-González JF. Association of Klotho with Coronary Artery Disease in Subjects with Type 2 Diabetes Mellitus and Preserved Kidney Function: A Case-Control Study. Int J Mol Sci 2023; 24:13456. [PMID: 37686263 PMCID: PMC10488180 DOI: 10.3390/ijms241713456] [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: 08/14/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Circulating Klotho levels are significantly reduced in subjects with type 2 diabetes mellitus (T2DM) and in kidney disease patients. In this work, the relationship between Klotho levels and the coronary artery disease (CAD) burden in subjects with T2DM and preserved kidney function was analyzed. For this, we performed a cross-sectional case-control study involving 133 subjects with T2DM and 200 age-, sex- and CAD-incidence-matched, non-diabetic patients undergoing non-emergency diagnostic coronary angiography. All of them were non-albuminuric and with normal glomerular filtration rates. The concentrations of serum Klotho, fibroblast growth factor 23, and inflammatory markers were also measured. As expected, the serum Klotho concentration was lower in the T2DM group (12.3% lower, p = 0.04). However, within the group of patients with T2DM, those subjects with CAD presented significantly higher Klotho levels than those without significant coronary stenosis (314.5 (6.15-562.81) vs. 458.97 (275.2-667.2) pg/mL; p = 0.02). Multiple regression analysis revealed that serum Klotho was positively related with stenosis values exclusively in subjects with T2DM (adjusted R2 = 0.153, p < 0.01). Moreover, logistic regression analysis showed that Klotho was positively associated with the presence of significant CAD in the group of T2DM patients (OR: 1.001; p = 0.041). Our data suggest that higher levels of circulating Klotho in subjects with T2DM and preserved kidney function are associated with the presence of significant CAD.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 382500 Santa Cruz de Tenerife, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
| | - Alberto Martín-Olivera
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.M.-F.); (A.G.-L.); (A.M.-O.)
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 382500 Santa Cruz de Tenerife, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
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21
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Hung KC, Yao WC, Liu YL, Yang HJ, Liao MT, Chong K, Peng CH, Lu KC. The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease. Biomedicines 2023; 11:2076. [PMID: 37509715 PMCID: PMC10377042 DOI: 10.3390/biomedicines11072076] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/21/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting.
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Affiliation(s)
- Kuo-Chin Hung
- Division of Nephrology, Department of Medicine, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
- Department of Pharmacy, Tajen University, Pingtung 907, Taiwan
| | - Wei-Cheng Yao
- Department of Anesthesiology, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
- Department of Medical Education and Clinical Research, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
| | - Yi-Lien Liu
- Department of Family Medicine, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
| | - Hung-Jen Yang
- Department of General Medicine, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
| | - Min-Tser Liao
- Department of Pediatrics, Taoyuan Armed Forces General Hospital Hsinchu Branch, Hsinchu City 300, Taiwan
- Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Keong Chong
- Division of Endocrinology and Metabolism, Department of Medicine, Min-Sheng General Hospital, Taoyuan City 330, Taiwan
| | - Ching-Hsiu Peng
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
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22
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Ostojic SM, Hillesund ER, Øverby NC, Vik FN, Medin AC. Individual nutrients and serum klotho levels in adults aged 40-79 years. Food Sci Nutr 2023; 11:3279-3286. [PMID: 37324910 PMCID: PMC10261765 DOI: 10.1002/fsn3.3310] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
Several dietary factors (including adherence to the Mediterranean diet or higher nut intake) seem to positively affect circulating antiaging Klotho protein levels; yet, a description of possible relationships between individual nutrients and Klotho activity has not been evaluated. We analyzed the association of dietary intake of individual macro- and micronutrients and nonnutritive food components with circulating Klotho levels in a sample of 40- to 79-year-old US adults. Data from the 2015-2016 National Health and Nutrition Examination Survey were analyzed. Nutrient/food component intakes were calculated in relation to total energy intake using the nutrient density method, and available pristine serum samples were analyzed for serum Klotho concentrations. The final study sample consisted of 2637 participants (mean age 59.0 ± 10.7 years; 52% women). Higher Klotho concentrations were found with higher intake of carbohydrates (p < .001), total sugars (p < .001), dietary fibers (p < .001), vitamin D (p = .05), total folates (p = .015), and copper (p = .018). The results of the regression analysis with a crude model showed significant associations among five nutrients/food components (carbohydrates, alcohol, total sugars, dietary fibers, and niacin) and soluble Klotho levels across the sample. After adjusting the models for age and gender, the nutrient/food component-Klotho association remained significant for carbohydrates, total sugars, and alcohol (p < .05). Dietary exposure to individual nutrients and nonnutritive food components appears to be associated with Klotho activity; however, additional research is needed to investigate the relationship between cause and effect in diet composition-Klotho interplay.
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Affiliation(s)
- Sergej M. Ostojic
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | | | - Nina C. Øverby
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | - Frøydis N. Vik
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
| | - Anine C. Medin
- Department of Nutrition and Public HealthUniversity of AgderKristiansandNorway
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23
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Hill C, Duffy S, Kettyle LM, McGlynn L, Sandholm N, Salem RM, Thompson A, Swan EJ, Kilner J, Rossing P, Shiels PG, Lajer M, Groop PH, Maxwell AP, McKnight AJ. Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes. Genes (Basel) 2023; 14:genes14051029. [PMID: 37239390 DOI: 10.3390/genes14051029] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/21/2023] [Accepted: 04/23/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10-6). Telomere length was also significantly reduced (p = 6.6 × 10-5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10-8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
| | - Seamus Duffy
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
| | - Laura M Kettyle
- Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast BT9 7AE, UK
| | - Liane McGlynn
- College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland
- Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, 00290 Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
| | - Rany M Salem
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA 92093, USA
| | - Alex Thompson
- School of Medicine, The Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Elizabeth J Swan
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
| | - Jill Kilner
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
| | - Peter Rossing
- Nordsjaellands Hospital, Hilleroed, Denmark and Health, Aarhus University, 8000 Aarhus, Denmark
- Steno Diabetes Center, 2730 Gentofte, Denmark
- Department of Clinical Medicine, University of Copenhagen, 1165 Copenhagen, Denmark
| | - Paul G Shiels
- School of Molecular Biosciences, Davidson Building, University of Glasgow, Glasgow G12 8QQ, UK
| | - Maria Lajer
- Steno Diabetes Center, 2730 Gentofte, Denmark
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland
- Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, 00290 Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3800, Australia
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, UK
| | - Amy Jayne McKnight
- Centre for Public Health, Queen's University of Belfast, Belfast BT12 6BA, UK
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24
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Mohamed OS, Abdel Baky NA, Sayed-Ahmed MM, Al-Najjar AH. Lactoferrin alleviates cyclophosphamide induced-nephropathy through suppressing the orchestration between Wnt4/β-catenin and ERK1/2/NF-κB signaling and modulating klotho and Nrf2/HO-1 pathway. Life Sci 2023; 319:121528. [PMID: 36828132 DOI: 10.1016/j.lfs.2023.121528] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023]
Abstract
AIMS Cyclophosphamide is an alkylating agent with vast arrays of therapeutic activity. Currently, its medical use is limited due to its numerous adverse events, including nephrotoxicity. This study aimed to follow the molecular mechanisms behind the potential renoprotective action of lactoferrin (LF) against cyclophosphamide (CP)-induced renal injury. MATERIALS AND METHODS For fulfillment of our aim, Spragw-Dwaly rats were orally administrated LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). KEY FINDINGS Treatment of CP-injured rats with LF significantly reduced the elevated creatinine and blood urea nitrogen (BUN), markedly upregulated Nrf2/HO-1 signaling with consequent increase in renal total antioxidant capacity (TAC) and decrease in renal malondialdehyde (MDA) level. Furthermore, LF treatment significantly reduced the elevated renal p-ERK1/2 expression, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB) levels in CP-treated animals. Interestingly, LF treatment downregulated Wnt4/β-catenin signaling and increased both renal klotho gene expression and serum klotho level. Furthermore, LF treatment reduced apoptosis in kidney tissue via suppressing GSK-3β expression and modulating caspase-3 and Bcl2 levels. Histopathological examination of kidney tissue confirmed the protective effect of LF against CP-induced renal injury. SIGNIFICANCE The present findings document the renoprotective effect of LF against CP-induced nephropathy, which may be mediated via suppressing ERK1/2/ NF-κB and Wnt4/β-catenin trajectories and enhancing klotho expression and Nrf2/HO-1 signaling.
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Affiliation(s)
- Ola S Mohamed
- Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Nayira A Abdel Baky
- Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
| | - Mohamed M Sayed-Ahmed
- Pharmacology and Experimental Oncology Unit, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Aya H Al-Najjar
- Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
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25
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Bover J, Massó E, Gifre L, Alfieri C, Soler-Majoral J, Fusaro M, Calabia J, Rodríguez-Pena R, Rodríguez-Chitiva N, López-Báez V, Sánchez-Baya M, da Silva I, Aguilar A, Bustos MC, Rodrigues N, Chávez-Iñiguez JS, Romero-González G, Valdivielso JM, Molina P, Górriz JL. Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines. Nutrients 2023; 15:1576. [PMID: 37049415 PMCID: PMC10097233 DOI: 10.3390/nu15071576] [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: 02/28/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.
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Affiliation(s)
- Jordi Bover
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Elisabet Massó
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Laia Gifre
- Rheumatology Service, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
| | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Jordi Soler-Majoral
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Maria Fusaro
- National Research Council (CNR), 56124 Pisa, Italy
- Department of Medicine, University of Padua, 35128 Padova, Italy
| | - Jordi Calabia
- Department of Nephrology, University Hospital Josep Trueta, 17007 Girona, Spain
| | - Rosely Rodríguez-Pena
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Néstor Rodríguez-Chitiva
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Víctor López-Báez
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Maya Sánchez-Baya
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Iara da Silva
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - Armando Aguilar
- Department of Nephrology, Instituto Mexicano del Seguro Social, Hospital General de Zona No. 2, Tuxtla Gutiérrez 29000, Mexico
| | - Misael C. Bustos
- Department of Nephrology, Pontificia Catholic University of Chile, Santiago 8331150, Chile
| | - Natacha Rodrigues
- Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Universitário Lisboa Norte, EPE, 1649-028 Lisboa, Portugal
| | - Jonathan S. Chávez-Iñiguez
- Department of Nephrology, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara 44280, Mexico
- Centro Universitario de Ciencias de la Salud CUCS, Guadalajara University, Guadalajara 44340, Mexico
| | - Gregorio Romero-González
- Department of Nephrology, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain
- REMAR-IGTP Group, Research Institute Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain
| | - José Manuel Valdivielso
- Grupo de Investigación Traslacional Vascular y Renal, Instituto de Investigación Biomédica IRBlleida, 25198 Lleida, Spain
| | - Pablo Molina
- Department of Nephrology, Hospital Universitario Dr Peset, Universitat de València Fisabio, 46017 Valencia, Spain
| | - José L. Górriz
- Department of Nephrology, University Hospital Clínico, INCLIVA, Valencia University, 46010 Valencia, Spain
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26
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Chu YT, Chen BH, Chen HH, Lee JC, Kuo TJ, Chiu HC, Lu WH. Hypoxia-Induced Kidney Injury in Newborn Rats. TOXICS 2023; 11:260. [PMID: 36977025 PMCID: PMC10053593 DOI: 10.3390/toxics11030260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 06/18/2023]
Abstract
Exposure to hypoxia during the early postnatal period can have adverse effects on vital organs. Neonatal Sprague-Dawley rats housed in a hypoxic chamber were compared to those in a normoxic chamber from postnatal days 0 to 7. Arterial blood was collected to evaluate renal function and hypoxia. Kidney morphology and fibrosis were evaluated using staining methods and immunoblotting. In the kidneys of the hypoxic group, protein expressions of hypoxia-inducible factor-1 were higher than those in the normoxic group. Hypoxic rats had higher levels of hematocrit, serum creatinine, and lactate than normoxic rats. Body weight was reduced, and protein loss of kidney tissue was observed in hypoxic rats compared to normoxic rats. Histologically, hypoxic rats showed glomerular atrophy and tubular injury. Renal fibrosis with collagen fiber deposition was observed in the hypoxic group. The expression of nicotinamide adenine dinucleotide phosphate oxidases was enhanced in the kidneys of hypoxic rats. Proteins involved in apoptosis were upregulated in the kidneys of hypoxic rats. An increase in the expression of pro-inflammatory cytokines was also observed in the kidneys of hypoxic rats. Hypoxic kidney injury in neonatal rats was associated with oxidative stress, inflammation, apoptosis, and fibrosis.
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Affiliation(s)
- Yi-Ting Chu
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Bo-Hau Chen
- Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan 32551, Taiwan
| | - Hsin-Hung Chen
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Jui-Chen Lee
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Tzu-Jiun Kuo
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Hsiang-Chin Chiu
- Department of Pediatrics, Pingtung Veterans General Hospital, Pingtung 91245, Taiwan
| | - Wen-Hsien Lu
- Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
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Jain RB. Associations between concentrations of serum α-klotho and selected urinary monohydroxy metabolites of polycyclic aromatic hydrocarbons: data for US adults aged 40-79 years. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:33298-33306. [PMID: 36474043 DOI: 10.1007/s11356-022-24565-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/30/2022] [Indexed: 06/17/2023]
Abstract
For the first time, the associations between urinary concentrations of oxidant polycyclic aromatic hydrocarbon (PAH) metabolites and serum concentrations of anti-oxidant α-klotho were estimated for US adults aged 40-79 years. Multivariate regression models with α-klotho as dependent variable and one of the urinary metabolite of PAH as independent variables were fitted. In the absence of albuminuria and normal (eGFR > 90 mL/min/1.73 m2) kidney function, 10% increases in concentrations of 2-hydroxynaphthalene, 9-hydroxyfluorene, and ∑PAH were associated with 0.25%, 0.32%, and 0.19% decreases in serum α-klotho concentrations. In the absence of albuminuria and near normal (60 < = eGFR < 90 mL/min/1.73 m2) kidney function, 10% increases in concentrations of 1-hydroxynaphthalene, 9-hydroxyfluorene, 1-hydroxyphenanthrene, and ∑PAH were associated with 0.17%, 0.38%, 0.34%, and 0.18% decreases in serum α-klotho concentrations. To what degree, these mild decreases in α-klotho are a matter of concern, is a subject ripe for discussion and additional investigations. When kidney function was normal or near normal but albuminuria was present, the associations between α-klotho and different metabolites of PAH were, more or less, randomly positive or negative and none reached statistical significance. To conclude, exposure to polycyclic aromatic hydrocarbons may result in reduced concentrations of α-klotho, an antiaging protein.
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Williams MJ, White SC, Joseph Z, Hruska KA. Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker. Front Physiol 2023; 14:1120308. [PMID: 36776982 PMCID: PMC9909112 DOI: 10.3389/fphys.2023.1120308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023] Open
Abstract
The chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex multi-component syndrome occurring during kidney disease and its progression. Here, we update progress in the components of the syndrome, and synthesize recent investigations, which suggest a potential mechanism of the bone-vascular paradox. The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. Among the factors produced by calcifying arteries, sclerostin secretion is especially enlightening. Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. Subsequent studies showing that inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu. Thus, the target of therapy in the chronic kidney disease-mineral bone disorder is not inhibition of sclerostin function, which would intensify vascular calcification. Rather, decreasing sclerostin production by decreasing the vascular osteoblastic/osteocytic transdifferentiation is the goal. This might decrease vascular calcification, decrease vascular stiffness, decrease cardiac hypertrophy, decrease sclerostin production, reduce serum sclerostin and improve skeletal remodeling. Thus, the therapeutic target of the chronic kidney disease-mineral bone disorder may be vascular osteoblastic transdifferentiation, and sclerostin levels may be a useful biomarker for the diagnosis of the chronic kidney disease-mineral bone disorder and the progress of its therapy.
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Affiliation(s)
- Matthew J. Williams
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Sarah C. White
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Zachary Joseph
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Keith A. Hruska
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
- Departments of Medicine and Cell Biology, Washington University, Saint Louis, MO, United States
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Systematic Review of the Treatment of Persistent Hyperparathyroidism Following Kidney Transplantation. Biomedicines 2022; 11:biomedicines11010025. [PMID: 36672533 PMCID: PMC9855347 DOI: 10.3390/biomedicines11010025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Chronic kidney disease-mineral and bone disorder is one of the complications associated with chronic kidney disease. About 10-50% of patients following kidney transplantation have persistent hyperparathyroidism. Hypercalcaemic hyperparathyroidism has a negative impact on the kidney transplant outcome; therefore, it requires treatment. The data regarding the treatment of persistent hyperparathyroidism provided in scientific publications are divergent and contradictory. Therefore, the aim of our systematic review was to evaluate the efficacy of persistent hyperparathyroidism treatment in patients following kidney transplantation. The Cochrane, PubMed, and Scopus databases were browsed independently by two authors. The search strategy included controlled vocabulary and keywords. The effectiveness of calcitriol, paricalcitol, cinacalcet, and parathyroidectomy was compared and analysed. The mean calcium and parathormone (PTH) concentrations per patient in the group of paricalcitol increased by 1.27% and decreased by 35.14% (n = 248); in the group of cinacalcet decreased by 12.09% and 32.16% (n = 368); and in the group of parathyroidectomy decreased by 19.06% and 86.49% (n = 15) at the end of the study compared to the baseline (n = 244, n = 342 and n = 15), respectively. Paricalcitol, cinacalcet, and parathyroidectomy decreased the intact PTH level. Cinacalcet and parathyroidectomy lowered calcium levels in renal transplant patients with hypercalcaemia. Conversely, paricalcitol increased the serum calcium concentration. Cinacalcet seems to be a good candidate in the treatment of post-transplant hyperparathyroidism.
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Alharbi KS, Afzal O, Altamimi ASA, Almalki WH, Kazmi I, Al-Abbasi FA, Alzarea SI, Makeen HA, Albratty M. A study of the molecular mechanism of quercetin and dasatinib combination as senolytic in alleviating age-related and kidney diseases. J Food Biochem 2022; 46:e14471. [PMID: 36268851 DOI: 10.1111/jfbc.14471] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 01/14/2023]
Abstract
Aging is a significant risk factor for the majority of prevalent human illnesses. The chance of having severe chronic conditions grows dramatically with advancing age. Indeed, more than 90% of people over 65 get at least one chronic disease, including diabetes, heart disease, malignancy, memory loss, and kidney disease, whereas more than 70% have two or more of these ailments. Mouse and human aging lead to increased senescent cells and decreased klotho concentrations. Mice lacking the protein α-klotho show faster aging, similar to human aging. α-Klotho upregulation extends life and slows or suppresses the onset of many age-related illnesses and kidney diseases. Like the consequences of α-klotho deficiency, senescent cell accumulation is linked to tissue dysfunction in various organs and multiple age-related kidney diseases. In addition, α-klotho and cell senescence are negatively and presumably mechanistically linked. Earlier research has demonstrated that klotho exerts its protective effects in age-related and kidney disease by interacting with Wnt ligands, serving as an endogenous antagonist of Wnt/β-catenin signaling. In addition, decreasing senescent cell burden with senolytics, a class of drugs that remove senescent cells selectively and extend the life span of mice. In this work, we are studying the molecular mechanism of the combination of quercetin and dasatinib as senolytic in easing age-related chronic renal illness by altering the level of klotho/Wnt/β-catenin. PRACTICAL APPLICATIONS: There is an inverse relationship between the onset and the development of age-related disorders and cellular senescence and Klotho. Earlier attempts to suppress transforming growth factor-beta 1 (TGF-β1) in kidney disease with anti-TGF-β1 antibodies were ineffective, and this should be kept in mind. Senolytic medications may benefit from targeting senescent cells, which enhances the protective factor α-klotho. In addition, our study provides a unique, translationally feasible route for creating orally active small compounds to enhance α-klotho, which may also be a valuable biomarker for age-related kidney disease. Additionally, other aspects of aging can be affected by senolytics, such as limiting age-related mitochondrial dysfunction, lowering inflammation and fibrosis, blunting reactive oxygen species (ROS) generation, decreasing deoxyribonucleic acid (DNA) damage, and reinforcing insulin sensitivity. Senolytic agents have been shown to increase adipose progenitor and cardiac progenitor cell activity in aging animals and animals with cellular senescence-related diseases, such as heart, brain, and kidney disease.
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Affiliation(s)
- Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
| | | | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
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Serum Phosphate Levels Modify the Impact of FGF23 Levels on Hemoglobin in Chronic Kidney Disease. Nutrients 2022; 14:nu14224842. [PMID: 36432528 PMCID: PMC9698012 DOI: 10.3390/nu14224842] [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: 10/04/2022] [Revised: 11/08/2022] [Accepted: 11/12/2022] [Indexed: 11/17/2022] Open
Abstract
Anemia is a complication of chronic kidney disease (CKD). Phosphate and fibroblast growth factor-23 (FGF23) have a close relationship, as both are related to the pathogenesis of anemia. However, the possible interplay between them regarding their effect on anemia has not been evaluated. This was a cross-sectional study of 896 participants from the NEFRONA study (273 CKD3, 246 CKD4-5, 282 dialysis and 95 controls). The levels of 25(OH) and 1,25(OH)2 vitamin D, intact FGF23 (iFGF23) and soluble Klotho were measured, together with standard blood biochemistries. Anemia was defined as hemoglobin levels < 13 g/dL in men and <12 g/dL in women. Patients with anemia (407, 45.4%) were younger, mostly men and diabetic; were in advanced CKD stages; had lower calcium, 1,25(OH)2 vitamin D and albumin levels; and had higher ferritin, phosphate, intact PTH, and iFGF23. An inverse correlation was observed between hemoglobin and both iFGF23 and phosphate. The multivariate logistic regression analyses showed that the adjusted risk of anemia was independently associated with higher serum phosphate and LogiFGF23 levels (ORs (95% CIs) of 4.33 (2.11−8.90) and 8.75 (3.17−24.2), respectively (p < 0.001)). A significant interaction between phosphate and iFGF23 (OR of 0.66 (0.53−0.83), p < 0.001) showed that the rise in the adjusted predicted risk of anemia with the increase in iFGF23 was steeper when phosphate levels were low. Phosphate levels acted as modifiers of the effect of iFGF23 concentration on anemia. Thus, the effect of the increase in iFGF23 levels was stronger when phosphate levels were low.
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Faienza MF, Pontrelli P, Brunetti G. Type 2 diabetes and bone fragility in children and adults. World J Diabetes 2022; 13:900-911. [PMID: 36437868 PMCID: PMC9693736 DOI: 10.4239/wjd.v13.i11.900] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/17/2022] [Accepted: 10/11/2022] [Indexed: 11/11/2022] Open
Abstract
Type 2 diabetes (T2D) is a global epidemic disease. The prevalence of T2D in adolescents and young adults is increasing alarmingly. The mechanisms leading to T2D in young people are similar to those in older patients. However, the severity of onset, reduced insulin sensitivity and defective insulin secretion can be different in subjects who develop the disease at a younger age. T2D is associated with different complications, including bone fragility with consequent susceptibility to fractures. The purpose of this systematic review was to describe T2D bone fragility together with all the possible involved pathways. Numerous studies have reported that patients with T2D show preserved, or even increased, bone mineral density compared with controls. This apparent paradox can be explained by the altered bone quality with increased cortical bone porosity and compr-omised mechanical properties. Furthermore, reduced bone turnover has been described in T2D with reduced markers of bone formation and resorption. These findings prompted different researchers to highlight the mechanisms leading to bone fragility, and numerous critical altered pathways have been identified and studied. In detail, we focused our attention on the role of microvascular disease, advanced glycation end products, the senescence pathway, the Wnt/β-catenin pathway, the osteoprotegerin/receptor-activator of nuclear factor kappa B ligand, osteonectin and fibroblast growth factor 23. The understanding of type 2 myeloid bone fragility is an important issue as it could suggest possible interventions for the prevention of poor bone quality in T2D and/or how to target these pathways when bone disease is clearly evident.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Paola Pontrelli
- Division of Nephrology, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari 70125, Italy
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Sarnak MJ, Auguste BL, Brown E, Chang AR, Chertow GM, Hannan M, Herzog CA, Nadeau-Fredette AC, Tang WHW, Wang AYM, Weiner DE, Chan CT. Cardiovascular Effects of Home Dialysis Therapies: A Scientific Statement From the American Heart Association. Circulation 2022; 146:e146-e164. [PMID: 35968722 DOI: 10.1161/cir.0000000000001088] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage kidney disease. Currently, thrice-weekly in-center hemodialysis for 3 to 5 hours per session is the most common therapy worldwide for patients with treated kidney failure. Outcomes with thrice-weekly in-center hemodialysis are poor. Emerging evidence supports the overarching hypothesis that a more physiological approach to administering dialysis therapy, including in the home through home hemodialysis or peritoneal dialysis, may lead to improvement in several cardiovascular risk factors and cardiovascular outcomes compared with thrice-weekly in-center hemodialysis. The Advancing American Kidney Health Initiative, which has a goal of increasing the use of home dialysis, is aligned with the American Heart Association's 2024 mission to champion a full and healthy life and health equity. We conclude that incorporation of interdisciplinary care models to increase the use of home dialysis therapies in an equitable manner will contribute to the ultimate goal of improving outcomes for patients with kidney failure and cardiovascular disease.
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Yao Y, He GY, Wu XJ, Wang CP, Luo XB, Zhao Y, Long Y. Association between environmental exposure to perchlorate, nitrate, and thiocyanate and serum α-Klotho levels among adults from the National Health and nutrition examination survey (2007–2014). BMC Geriatr 2022; 22:740. [PMID: 36096772 PMCID: PMC9465863 DOI: 10.1186/s12877-022-03444-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/08/2022] [Indexed: 11/10/2022] Open
Abstract
Background & aims Aging is a pathophysiological process driven by a diverse set of complex biological processes, and environmental pollution plays an important role in this process. This study aimed to explore the association between serum α-Klotho levels and urinary perchlorate, nitrate, and thiocyanate levels. Methods This secondary dataset analysis included 4875 participants (mean age, 57.69 year; male, 49.58%; non-Hispanic White, 47.67%) from the US National Health and Nutrition Examination Survey (2007–2014). Enzyme-linked immunosorbent assay was used to quantify α-Klotho levels, and ion chromatography coupled with electrospray tandem mass spectrometry was used to quantify thiocyanate, nitrate, and perchlorate levels. Multivariate linear regression models were applied to estimate the association between perchlorate, nitrate, and thiocyanate levels and serum α-Klotho levels. Results Urinary thiocyanate levels were negatively associated with α-Klotho levels (β = − 0.006; 95% confidence interval, − 0.010 to − 0.003; P = 0.0004) after adjusting for age, sex, body mass index, race, alcohol consumption, estimated glomerular filtration rate, underlying disease, physical activity, smoking status, usual energy intake, and urinary creatinine and serum cotinine levels and mutual adjustment of urinary perchlorate, urinary nitrate, and urinary thiocyanate levels. The α-Klotho level in participants in the highest quartile was higher by 50.567 ng/mL (β = 50.567; 95% confidence interval, 14.407 to 86.726; P = 0.009) than that in participants in the lowest quartile of urinary perchlorate. A linear relationship was observed between urinary thiocyanate and α-Klotho levels. Conclusions Urinary thiocyanate levels were negatively associated with serum α-Klotho levels. Urinary thiocyanate should be further investigated as a potential mediator of aging and age-related diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-022-03444-2.
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35
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Jain RB, Ducatman A. Associations between the concentrations of α-klotho and selected perfluoroalkyl substances in the presence of eGFR based kidney function and albuminuria: Data for US adults aged 40-79 years. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 838:155994. [PMID: 35595139 DOI: 10.1016/j.scitotenv.2022.155994] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023]
Abstract
Exposures to per- and polyfluoroalkyl substances (PFAS) cause oxidative stress, a risk factor for tissue damage leading to kidney and cardiovascular diseases. The antiaging protein klotho is known to act as an anti-oxidative agent, and how klotho homeostasis interacts with PFAS has not been reported. This study among 3981 US adults aged 40-79 years old evaluated relationships of internal PFAS contamination to α-klotho across stages of estimated glomerular filtration rate or eGFR-based kidney function and albuminuria defined as urinary albumin creatinine ratio of >30 mg/g creatinine. In the absence of albuminuria and when eGFR based kidney function was in stage GF-1 (eGFR ≥ 90 mL/min/1.73 m2), statistically significant inverse associations between α-klotho and PFNA (β = -0.04930, p < 0.01), PFDA (β = -0.03307, p = 0.02), and PFUnDA (β = -0.03451, p = 0.01), PFHxS (β = -0.03011, p = 0.04) and PFOS (β = -0.03126, p = 0.03) were noted. No associations between α-klotho and PFAS were observed when kidney function was in stages GF-2 (60 ≤ eGFR < 90 mL/min/1.73 m2) or GF-3A (45 ≤ eGFR < 60 mL/min/1.73 m2) in the presence or absence of albuminuria. Unexpectedly, however, in the absence of albuminuria, with kidney function in stage GF-3B/4 (15 ≤ eGFR < 45 mL/min/1.73 m2), associations were positive between α-klotho and PFOA (β = 0.20989, p < 0.01), PFNA (β = 0.18373, p < 0.1), PFDA (β = 0.20413, p < 0.01), PFUnDA (β = 0.17660, p < 0.01), and PFOS (β = 0.14267, p < 0.01). The inverse relationship of PFAS to the antioxidant protein α-klotho in those with healthy kidney function has not been previously reported and should be evaluated in other populations.
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Affiliation(s)
- Ram B Jain
- Independent Researcher, Loganville, GA, USA.
| | - Alan Ducatman
- West Virginia School of Public Health, Morgantown, WV, USA
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Cai Y, Hu J, He M. KL-FGF23-VD Axis in Improving Late-Onset Alzheimer's Disease by Modulating IKK/NF- κB Signal Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:3100621. [PMID: 36118087 PMCID: PMC9481392 DOI: 10.1155/2022/3100621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 11/23/2022]
Abstract
Materials and Methods LOAD rats and Aβ microglia were constructed by using Aβ 1-40 and IBO mixture. The effect of KL-FGF23-VD axis on LOAD was investigated by transfecting overexpressing and interfering with KL gene adenovirus, and IKK-16 was added to Aβ microglia to explore the effect of KL-FGF23-VD axis on regulation of IKK/NF-κB signaling pathway. Results The results showed that, in KL-OE group, FGF23 was decreased in the hippocampus of LOAD rats compared with control and KL-si, and the trend was opposite in the KL-si group. The KL-FGF23-VD axis can alleviate inflammatory response, reduce the deposition of Aβ, and inhibit activation of the NF-κB pathway and neuron apoptosis in brain tissue of LOAD rats. In Aβ microglia, the expression of KL-FGF23-VD axis was consistent with animal experiments. The KL-FGF23-VD axis can inhibit the expression of Aβ microglia inflammatory factors and the activation of microglia and NF-κB pathway. Meanwhile, IKK expression was decreased in KL-OE group compared with KL-si and Control. In the IKK-16 addition group, the ability of KL-FGF23-VD axis to inhibit the activation of microglia and NF-κB pathway was enhanced. Conclusions These findings suggest a potential role of the KL-FGF23-VD axis in AD treatment by regulating the IKK/NF-κB pathway.
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Affiliation(s)
- Yingying Cai
- Department of Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Jiali Hu
- Department of Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Mingjie He
- Medical Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
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Imenez Silva PH, Mohebbi N. Kidney metabolism and acid-base control: back to the basics. Pflugers Arch 2022; 474:919-934. [PMID: 35513635 PMCID: PMC9338915 DOI: 10.1007/s00424-022-02696-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 01/18/2023]
Abstract
Kidneys are central in the regulation of multiple physiological functions, such as removal of metabolic wastes and toxins, maintenance of electrolyte and fluid balance, and control of pH homeostasis. In addition, kidneys participate in systemic gluconeogenesis and in the production or activation of hormones. Acid-base conditions influence all these functions concomitantly. Healthy kidneys properly coordinate a series of physiological responses in the face of acute and chronic acid-base disorders. However, injured kidneys have a reduced capacity to adapt to such challenges. Chronic kidney disease patients are an example of individuals typically exposed to chronic and progressive metabolic acidosis. Their organisms undergo a series of alterations that brake large detrimental changes in the homeostasis of several parameters, but these alterations may also operate as further drivers of kidney damage. Acid-base disorders lead not only to changes in mechanisms involved in acid-base balance maintenance, but they also affect multiple other mechanisms tightly wired to it. In this review article, we explore the basic renal activities involved in the maintenance of acid-base balance and show how they are interconnected to cell energy metabolism and other important intracellular activities. These intertwined relationships have been investigated for more than a century, but a modern conceptual organization of these events is lacking. We propose that pH homeostasis indissociably interacts with central pathways that drive progression of chronic kidney disease, such as inflammation and metabolism, independent of etiology.
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Affiliation(s)
- Pedro Henrique Imenez Silva
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
- National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.
| | - Nilufar Mohebbi
- National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland
- Praxis Und Dialysezentrum Zurich, Zurich, Switzerland
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38
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Jain RB. Serum klotho and its associations with blood and urine cadmium and lead across various stages of glomerular function: data for US adults aged 40-79 years. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:57412-57420. [PMID: 35349059 DOI: 10.1007/s11356-022-19900-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/21/2022] [Indexed: 06/14/2023]
Abstract
Exposures to cadmium and lead can cause oxidative stress, leading to tissue damage resulting in kidney and cardiovascular diseases. The antiaging protein klotho, on the other hand, is known to act as an anti-oxidative agent. How klotho homeostasis interacts with exposure to cadmium and lead has not been reported. Thus, this study was carried to investigate associations of serum klotho with blood and urine cadmium and lead in US adults aged 40-79 years across stages of eGFR-based kidney function and albuminuria defined as urinary albumin/creatinine ratio of > 30 mg/g creatinine. As long as the kidney function was normal (eGFR ≥ 90 mL/min/1.73 m2) or near normal (60 ≤ eGFR < 90 mL/min/1.73 m2), there was no evidence of an association between cadmium exposure and klotho concentrations irrespective of the presence/absence of albuminuria. During kidney dysfunction (15 ≤ eGFR < 60 mL/min/1.73 m2), 10% increases in blood cadmium concentrations resulted in decreases in klotho concentrations between 0.27 and 0.84%. In addition, during severe kidney dysfunction (15 ≤ eGFR < 45 mL/min/1.73 m2), a positive association between urine cadmium and serum klotho concentrations was observed. In the absence of albuminuria and when kidney function was normal or near normal, 10% increases in blood lead concentrations were observed to be associated with modest decreases between 0.28% and 0.37% in serum klotho concentrations. Similar results were observed between the concentrations of urine lead and serum klotho during kidney dysfunction.
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Affiliation(s)
- Ram B Jain
- , 4331 Kendrick Circle, Loganville, GA, 30019, USA.
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Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations. FRONTIERS IN AGING 2022; 3:931331. [PMID: 35903083 PMCID: PMC9314780 DOI: 10.3389/fragi.2022.931331] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/06/2022] [Indexed: 12/06/2022]
Abstract
The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.
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Affiliation(s)
- Gérald J. Prud’homme
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON, Canada
- *Correspondence: Gérald J. Prud’homme,
| | - Mervé Kurt
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON, Canada
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China
- Shanghai Yinuo Pharmaceutical Co., Ltd., Shanghai, China
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Association between Dietary Inflammatory Index and serum Klotho concentration among adults in the United States. BMC Geriatr 2022; 22:528. [PMID: 35761232 PMCID: PMC9238083 DOI: 10.1186/s12877-022-03228-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/10/2022] [Indexed: 02/08/2023] Open
Abstract
Background Klotho is a hormone that emerges as an antiaging biomarker. However, the influence of the dietary pattern’s inflammatory potential on serum Klotho levels in human populations, especially in a general adult population, remains unknown. This study aimed to evaluate the relationship between the dietary inflammatory index (DII) and serum Klotho concentrations in individuals living in the United States. Methods From the 2007–2016 National Health and Nutrition Examination Survey database, data of participants who completed the full 24-h dietary history and underwent serum Klotho testing were analyzed. The association between DII and serum Klotho concentrations was estimated using multivariable linear regression models. We also conducted segmented regression model to examine the threshold effect of DII on serum Klotho concentrations. Results A total of 10,928 participants were included, with a median serum Klotho concentration of 805.20 pg/mL (IQR: 657.58 − 1001.12) and a median DII of 1.43 (IQR: − 0.16 − 2.82). Multivariable regression showed that participants with high DII scores were associated with low serum Klotho concentrations; when classifying DII into quartiles, after full adjustment, participants in DII quartiles 3 and 4 showed a decrease in Klotho levels (25.27 and 12.44 pg/ml, respectively) compared with those in the lowest quartile (quartile 1) (95% CI: − 41.80, − 8.73 and − 29.83, 4.95, respectively; P for trend = 0.036). The segmented regression showed that the turning point value of DII was − 1.82 (95% CI: − 2.32, − 0.80). A 1-unit increase in DII was significantly associated with lower Klotho levels by − 33.05 (95% CI: − 52.84, − 13.27; P = 0.001) when DII ranges from − 5.18 to − 1.82; however, the relationship was not significant when DII ranges from − 1.82 to 5.42 (P > 0.05). Furthermore, stratified analyses indicated that the observed associations between DII and serum Klotho concentration were stronger among those aged ≥ 56 years, those with normal weight, and those without chronic kidney disease (P for interaction = 0.003, 0.015, and 0.041, respectively). Conclusions In summary, we indicated that there was a dose–response relationship between DII and serum Klotho concentrations, suggesting that adhering to an anti-inflammatory diet has beneficial effects on aging and health by increasing the serum Klotho concentration. Supplementary Information The online version contains supplementary material available at 10.1186/s12877-022-03228-8.
klotho deficiency linked to multiple premature-aging syndromes and a short lifespan Proinflammatory cytokines, including TNF-α, IFN-γ, and IL-6, downregulate α-Klotho gene expression Dietary Inflammatory Index was developed as a tool to determine the inflammatory potential of diet We found that there was a dose–response relationship between DII and circulating concentrations of klotho in a nationally representative population of American adults.
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Noh K, Chow ECY, Quach HP, Groothuis GMM, Tirona RG, Pang KS. Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters. AAPS J 2022; 24:71. [PMID: 35650371 DOI: 10.1208/s12248-022-00719-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/16/2022] [Indexed: 11/30/2022] Open
Abstract
The vitamin D receptor (VDR), in addition to other nuclear receptors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is involved in the regulation of enzymes, transporters and receptors, and therefore intimately affects drug disposition, tissue health, and the handling of endogenous and exogenous compounds. This review examines the role of 1α,25-dihydroxyvitamin D3 or calcitriol, the natural VDR ligand, on activation of the VDR and its crosstalk with other nuclear receptors towards the regulation of enzymes and transporters, notably many of the cytochrome P450s including CYP3A4 and sulfotransferase 2A1 (SULT2A1) as well as cholesterol 7α-hydroxylase (CYP7A1). Moreover, the VDR upregulates the intestinal channel, TRPV6, for calcium absorption, LDL receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) in brain for β-amyloid peptide efflux and influx, the sodium phosphate transporters (NaPi), the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporters (OSTα-OSTβ) for bile acid absorption and efflux, respectively, the renal organic anion transporter 3 (OAT3) and several of the ATP-binding cassette protein transporters-the multidrug resistance protein 1 (MDR1) and the multidrug resistance-associated proteins (MRPs). Hence, the role of the VDR is increasingly being recognized for its therapeutic potential and pharmacologic activity, giving rise to drug-drug interactions (DDI). Therapeutically, ligand-activated VDR shows anti-inflammatory effects towards the suppression of inflammatory mediators, improves cognition by upregulating amyloid-beta (Aβ) peptide clearance in brain, and maintains phosphate, calcium, and parathyroid hormone (PTH) balance and kidney function and bone health, demonstrating the crucial roles of the VDR in disease progression and treatment of diseases.
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Affiliation(s)
- Keumhan Noh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts, 02142, USA
| | - Edwin C Y Chow
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Holly P Quach
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada
| | - Geny M M Groothuis
- Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Rommel G Tirona
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada
| | - K Sandy Pang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
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Kusumi K, Kremsdorf R, Kakajiwala A, Mahan JD. Pediatric Mineral and Bone Disorder of Chronic Kidney Disease and Cardiovascular Disease. Adv Chronic Kidney Dis 2022; 29:275-282. [PMID: 36084974 DOI: 10.1053/j.ackd.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 03/29/2022] [Accepted: 04/05/2022] [Indexed: 11/11/2022]
Abstract
Chronic kidney disease is common and causes significant morbidity including shortened lifespans and decrease in quality of life for patients. The major cause of mortality in chronic kidney disease is cardiovascular disease. Cardiovascular disease within the chronic kidney disease population is closely tied with disordered calcium and phosphorus metabolism and driven in part by renal bone disease. The complex nature of renal, bone, and cardiovascular diseases was renamed as mineral and bone disorder of chronic kidney disease to encompass how bone disease drives vascular calcification and contributes to the development of long-term cardiovascular disease, and recent data suggest that managing bone disease well can augment and improve cardiovascular disease status. Pediatric nephrologists have additional obstacles in optimal mineral and bone disorder of chronic kidney disease management such as linear growth and skeletal maturation. In this article, we will discuss cardiovascular and bone diseases in chronic kidney disease and end-stage kidney disease patients with a focus on pediatric issues and concerns.
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Affiliation(s)
- Kirsten Kusumi
- Department of Pediatric Nephrology, Akron Children's Hospital, Akron, OH.
| | - Robin Kremsdorf
- Pediatric Nephrology and Hypertension, Hasbro Children's Hospital, Providence, RI
| | - Aadil Kakajiwala
- Departments of Pediatric Critical Care Medicine and Nephrology, Children's National Hospital, Washington, DC
| | - John D Mahan
- Division of Nephrology and Hypertension at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH
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Impact of klotho on the expression of SRGAP2a in podocytes in diabetic nephropathy. BMC Nephrol 2022; 23:151. [PMID: 35436879 PMCID: PMC9014571 DOI: 10.1186/s12882-022-02765-z] [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: 11/28/2021] [Accepted: 03/30/2022] [Indexed: 11/14/2022] Open
Abstract
Background Diabetic nephropathy (DN) is the major cause of kidney failure, and glomerular podocytes play critical roles in the pathogenesis of DN by maintaining the glomerular structure and filtration barrier. Klotho and Slit-Robo GTP activating protein 2a (SRGAP2a) have been indicated to play protective roles in reducing kidney injury, but whether there is an internal relationship between these two factors is unclear. Methods In this study, we cultured differentiated rat podocytes in vitro and measured the SRGAP2a expressions by immunofluorescence staining, quantitative real-time PCR (qRT-PCR) and western blotting, after siRNA-mediated transforming growth factor β1 (TGF-β1) silencing, TGF-β1 overexpression and in the presence of a reactive oxygen species (ROS) inhibitor. And we detected the expressions of SRGAP2a, small mother against decapentaplegic (Smad)2/3, phosphorylated-Smad2/3 (p-Smad2/3), Smad7, and NAD(P)H oxidase 4 (NOX4), ROS levels and podocyte cytoskeletal remodelling under high glucose (HG) and exogenous klotho conditions. In addition, we performed haematoxylin–eosin (HE) staining and immunohistochemistry with diabetic rat models to confirm the in vitro results. Results The results indicated that SRGAP2a expression was significantly upregulated under siRNA-mediated TGF-β1 silencing conditions or after adding a ROS inhibitor, but significantly downregulated with TGF-β1 overexpression, in the presence of HG. The supplementation of exogenous klotho under HG conditions significantly increased the SRGAP2a expression, remodelled the actin cytoskeleton and altered the expressions of Smad2/3, p-Smad2/3, Smad7 and NOX4 and reduced the ROS generation in podocytes. Moreover, klotho administration protected kidney injury in DN rats. Conclusions This study indicated that klotho may modulate the expression of SRGAP2a by regulating the ROS and TGF-β1 signalling pathways and provided theoretical support for klotho protein as a novel therapeutic strategy for treating DN patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02765-z.
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Ahmed RF, Okasha AM, Hafiz SHI, Abdel-Gaber SA, Yousef RKM, Sedik WF. Guanosine protects against glycerol-induced acute kidney injury via up-regulation of the klotho gene. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:399-404. [PMID: 35656176 PMCID: PMC9148399 DOI: 10.22038/ijbms.2022.60579.13428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 03/09/2022] [Indexed: 12/02/2022]
Abstract
Objectives Acute Kidney Injury (AKI) is characterized by a rapid and reversible decline in renal function with a rapid decrease in Glomerular Filtration Rate (GFR), which is associated with high mortality. Rhabdomyolysis accounts for 10-40% of AKI, to which the therapeutic approach is limited. Klotho is a protein that modulates sodium-phosphate co-transporters, ion channels that have been reported to have a renal protective effect. Guanosine, a purine nucleoside, has already been reported to have a renal protective effect; however, the mechanism of such protection and its relation to Klotho modification has not been evaluated yet. This study aims to evaluate the mechanism of the protective effect of guanosine against rhabdomyolysis-induced AKI and its relation to the expression of the Klotho gene. Materials and Methods In the current study, rats were divided into three groups: control, glycerol-induced AKI, and guanosine-treated. Serum urea and creatinine levels, renal tissue Total Antioxidant Capacity (TAC), and Klotho and Cystatin C genes expression were evaluated. Furthermore, caspase-3 immunostaining and histopathological evaluations were done. Results Results showed that guanosine treatment resulted in a significant reduction in serum urea and creatinine, Cystatin C genes expression, and caspase-3 immunoexpression, and an increase in TAC and Klotho genes expression. Results also revealed an improvement of renal histopathology when compared with the glycerol-induced AKI group. Conclusion Guanosine may be a promising agent in the treatment of rhabdomyolysis-induced AKI. The proposed mechanism for guanosine may be through its ability to enhance Klotho gene expression in renal tissue, with subsequent antioxidant and anti-apoptotic activity.
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Affiliation(s)
- Rasha F. Ahmed
- Department of Medical Biochemistry, Faculty of Medicine, Minia University, 61511, Minia, Egypt
| | - Ahmed M. Okasha
- Department of Medical Biochemistry, Faculty of Medicine, Minia University, 61511, Minia, Egypt
| | | | - Seham A. Abdel-Gaber
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511, Minia, Egypt
| | | | - Wael F Sedik
- Department of Medical Biochemistry, Faculty of Medicine, Minia University, 61511, Minia, Egypt
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Steinbach EJ, Harshman LA. Impact of Chronic Kidney Disease on Brain Structure and Function. Front Neurol 2022; 13:797503. [PMID: 35280279 PMCID: PMC8913932 DOI: 10.3389/fneur.2022.797503] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/24/2022] [Indexed: 12/29/2022] Open
Abstract
Chronic kidney disease (CKD) affects more than 37 million American adults. Adult-onset CKD is typically attributed to acquired comorbidities such as aging, type II diabetes, and cardiovascular disease. Conversely, congenital abnormalities of the kidney and urinary tract are the most common cause of CKD in children. Both adult and pediatric patients with CKD are at risk for neurocognitive dysfunction, particularly in the domain of executive function. The exact mechanism for neurocognitive dysfunction in CKD is not known; however, it is conceivable that the multisystemic effects of CKD—including hypertension, acidosis, anemia, proteinuria, and uremic milieu—exert a detrimental effect on the brain. Quantitative neuroimaging modalities, such as magnetic resonance imaging (MRI), provide a non-invasive way to understand the neurobiological underpinnings of cognitive dysfunction in CKD. Adult patients with CKD show differences in brain structure; however, much less is known about the impact of CKD on neurodevelopment in pediatric patients. Herein, this review will summarize current evidence of the impact of CKD on brain structure and function and will identify the critical areas for future research that are needed to better understand the modifiable risk factors for abnormal brain structure and function across both pediatric and adult CKD populations.
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Affiliation(s)
- Emily J. Steinbach
- Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Lyndsay A. Harshman
- Division of Nephrology, Dialysis, and Transplantation, University of Iowa Stead Family Children's Hospital, Iowa City, IA, United States
- *Correspondence: Lyndsay A. Harshman
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Park MY, Le Henaff C, Sitara D. Administration of α-Klotho Does Not Rescue Renal Anemia in Mice. Front Pediatr 2022; 10:924915. [PMID: 35813388 PMCID: PMC9259788 DOI: 10.3389/fped.2022.924915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 12/05/2022] Open
Abstract
Renal anemia is a common complication in chronic kidney disease (CKD), associated with decreased production of erythropoietin (EPO) due to loss of kidney function, and subsequent decreased red blood cell (RBC) production. However, many other factors play a critical role in the development of renal anemia, such as iron deficiency, inflammation, and elevated fibroblast growth factor 23 (FGF23) levels. We previously reported that inhibition of FGF23 signaling rescues anemia in mice with CKD. In the present study we sought to investigate whether α-Klotho deficiency present in CKD also contributes to the development of renal anemia. To address this, we administered α-Klotho to mice with CKD induced by an adenine-rich diet. Mice were sacrificed 24 h after α-Klotho injection, and blood and organs were collected immediately post-mortem. Our data show that α-Klotho administration had no beneficial effect in mice with CKD-associated anemia as it did not increase RBC numbers and hemoglobin levels, and it did not stimulate EPO secretion. Moreover, α-Klotho did not improve iron deficiency and inflammation in CKD as it had no effect on iron levels or inflammatory markers. Interestingly, Klotho supplementation significantly reduced the number of erythroid progenitors in the bone marrow and downregulated renal Epo and Hif2α mRNA in mice fed control diet resulting in reduced circulating EPO levels in these mice. In addition, Klotho significantly decreased intestinal absorption of iron in control mice leading to reduced serum iron and transferrin saturation levels. Our findings demonstrate that α-Klotho does not have a direct role in renal anemia and that FGF23 suppresses erythropoiesis in CKD via a Klotho-independent mechanism. However, in physiological conditions α-Klotho appears to have an inhibitory effect on erythropoiesis and iron regulation.
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Affiliation(s)
- Min Young Park
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States
| | - Carole Le Henaff
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States
| | - Despina Sitara
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, United States.,Medicine, NYU School of Medicine, New York, NY, United States
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Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence. Toxins (Basel) 2021; 14:toxins14010008. [PMID: 35050985 PMCID: PMC8780792 DOI: 10.3390/toxins14010008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 12/28/2022] Open
Abstract
Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs).
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Franco ML, Beyerstedt S, Rangel ÉB. Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics 2021; 14:11. [PMID: 35056905 PMCID: PMC8778857 DOI: 10.3390/pharmaceutics14010011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high financial burden for the health system. Studies have indicated Klotho as a promising therapeutic approach for these conditions. Klotho reduces inflammation, oxidative stress and fibrosis and counter-regulates the renin-angiotensin-aldosterone system. In CKD and AKI, Klotho expression is downregulated from early stages and correlates with disease progression. Therefore, the restoration of its levels, through exogenous or endogenous pathways, has renoprotective effects. An important strategy for administering Klotho is through mesenchymal stem cells (MSCs). In summary, this review comprises in vitro and in vivo studies on the therapeutic potential of Klotho for the treatment of CKD and AKI through the administration of MSCs.
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Affiliation(s)
- Marcella Liciani Franco
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Érika Bevilaqua Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
- Nephrology Division, Federal University of São Paulo, Sao Paulo 04038-901, Brazil
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Assessing and counteracting fibrosis is a cornerstone of the treatment of CKD secondary to systemic and renal limited autoimmune disorders. Autoimmun Rev 2021; 21:103014. [PMID: 34896651 DOI: 10.1016/j.autrev.2021.103014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022]
Abstract
Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality worldwide. Besides the higher prevalence of diabetes, hypertension and aging worldwide, immune mediated disorders remain an important cause of kidney disease and are especially prevalent in young adults. Regardless of the initial insult, final pathway to CKD and kidney failure is always the loss of normal tissue and fibrosis development, in which the dynamic equilibrium between extracellular matrix synthesis and degradation is disturbed, leading to excessive production and accumulation. During fibrosis, a multitude of cell types intervene at different levels, but myofibroblasts and inflammatory cells are considered critical in the process. They exert their effects through different molecular pathways, of which transforming growth factor β (TGF-β) has demonstrated to be of particular importance. Additionally, CKD itself promotes fibrosis due to the accumulation of toxins and hormonal changes, and proteinuria is simultaneously a manifestation of CKD and a specific driver of renal fibrosis. Pathways involved in renal fibrosis and CKD are closely interrelated, and although important advances have been made in our knowledge of them, it is still necessary to translate them into clinical practice. Given the complexity of this process, it is highly likely that its treatment will require a multi-target strategy to control the origin of the damage but also the mechanisms that perpetuate it. Fortunately, rapid technology development over the last years and new available drugs in the nephrologist's armamentarium give reasons for optimism that more personalized assistance for CKD and renal fibrosis will appear in the future.
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Kale A, Sankrityayan H, Anders HJ, Gaikwad AB. Klotho in kidney diseases: A crosstalk between the renin-angiotensin system and endoplasmic reticulum stress. Nephrol Dial Transplant 2021; 38:819-825. [PMID: 34850136 DOI: 10.1093/ndt/gfab340] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Indexed: 11/15/2022] Open
Abstract
Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e., α-Klotho, β-Klotho, and γ-Klotho with distinct organ-specific expression and functions in the body. Here we focus on α-Klotho (mentioned as 'Klotho' only), abundantly expressed by the distal and proximal convoluted tubules of the kidney. Significant decline in systemic and renal Klotho level is a new hallmark for kidney disease progression. Emerging research portrays Klotho as a promising diagnostic as well as a therapeutic target for diabetic and non-diabetic kidney disease. Even so, the underlying mechanisms of Klotho regulation and the strategies to restore its systemic as well as the renal level are still lacking. Angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs) are the current standard of care for kidney diseases where the molecular mechanisms for their nephroprotective action are still ambiguous. Moreover, endoplasmic reticulum stress (ER stress) also plays a crucial role in kidney disease progression. Few studies have claimed that RAAS has a direct relation with ER stress generation and vice versa in kidney disease. Interestingly, RAAS and ER stress modulation is associated with Klotho regulation in kidney disease. Here we focus on how the RAAS and ER stress connects with Klotho regulation in kidney disease. We also discuss Klotho and ER stress in an alliance with the concept of hemodynamic and metabolic overload in kidney disease. In addition, we highlight novel approaches to implement Klotho as a therapeutic target via RAAS and ER stress modulation for the treatment of diabetic and non-diabetic kidney disease.
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Affiliation(s)
- Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
| | - Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, India
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