Klotho's Impact on Diabetic Nephropathy and Its Emerging Connection to Diabetic Retinopathy

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2023 May 5

PMID 37143722

Authors

Anqi Tang

Yu Zhang

Ling Wu

Yong Lin

Lizeyu Lv

Liangbin Zhao

Bojun Xu

Youqun Huang

Mingquan Li

Affiliations

Soon will be listed here.

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide and is a significant burden on healthcare systems. α-klotho (klotho) is a protein known for its anti-aging properties and has been shown to delay the onset of age-related diseases. Soluble klotho is produced by cleavage of the full-length transmembrane protein by a disintegrin and metalloproteases, and it exerts various physiological effects by circulating throughout the body. In type 2 diabetes and its complications DN, a significant decrease in klotho expression has been observed. This reduction in klotho levels may indicate the progression of DN and suggest that klotho may be involved in multiple pathological mechanisms that contribute to the onset and development of DN. This article examines the potential of soluble klotho as a therapeutic agent for DN, with a focus on its ability to impact multiple pathways. These pathways include anti-inflammatory and oxidative stress, anti-fibrotic, endothelial protection, prevention of vascular calcification, regulation of metabolism, maintenance of calcium and phosphate homeostasis, and regulation of cell fate through modulation of autophagy, apoptosis, and pyroptosis pathways. Diabetic retinopathy shares similar pathological mechanisms with DN, and targeting klotho may offer new insights into the prevention and treatment of both conditions. Finally, this review assesses the potential of various drugs used in clinical practice to modulate klotho levels through different mechanisms and their potential to improve DN by impacting klotho levels.

Citing Articles

Mechanisms, Biomarkers, and Treatment Approaches for Diabetic Kidney Disease: Current Insights and Future Perspectives.

Joumaa J, Raffoul A, Sarkis C, Chatrieh E, Zaidan S, Attieh P J Clin Med. 2025; 14(3).

PMID: 39941397 PMC: 11818458. DOI: 10.3390/jcm14030727.

Global research hotspots and trends in oxidative stress-related diabetic nephropathy: a bibliometric study.

Wang X, Wu Z, He T, Chen X, Jin X, Zuo C Front Endocrinol (Lausanne). 2025; 15:1451954.

PMID: 39866738 PMC: 11757133. DOI: 10.3389/fendo.2024.1451954.

Inverse association between serum klotho levels and C-reactive protein levels in the US population: a cross-sectional study.

Peng X, Hu Y, Xu J, Chen L, Ren W, Cai W BMC Cardiovasc Disord. 2024; 24(1):687.

PMID: 39614159 PMC: 11606063. DOI: 10.1186/s12872-024-04375-z.

α-Klotho prevents diabetic retinopathy by reversing the senescence of macrophages.

Li Q, Wang P, Gong Y, Xu M, Wang M, Luan R Cell Commun Signal. 2024; 22(1):449.

PMID: 39327553 PMC: 11426092. DOI: 10.1186/s12964-024-01838-w.

A PDE1 inhibitor, vinpocetine, ameliorates epithelial-mesenchymal transition and renal fibrosis in adenine-induced chronic kidney injury in rats by targeting the DNMT1/Klotho/β-catenin/Snail 1 and MMP-7 pathways.

Abdelfattah A, Mohammed Z, Talaat A, Samy W, Eldesoqui M, Elgarhi R Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39276250 DOI: 10.1007/s00210-024-03393-0.

References

Ji B, Wei H, Ding Y, Liang H, Yao L, Wang H . Protective potential of klotho protein on diabetic retinopathy: Evidence from clinical and in vitro studies. J Diabetes Investig. 2019; 11(1):162-169. PMC: 6944830. DOI: 10.1111/jdi.13100. View

Liu L, Liu Y, Zhang Y, Bi X, Nie L, Liu C . High phosphate-induced downregulation of PPARγ contributes to CKD-associated vascular calcification. J Mol Cell Cardiol. 2017; 114:264-275. DOI: 10.1016/j.yjmcc.2017.11.021. View

Ide N, Olauson H, Sato T, Densmore M, Wang H, Hanai J . In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling. Kidney Int. 2016; 90(2):348-362. DOI: 10.1016/j.kint.2016.04.009. View

Takenaka T, Kobori H, Miyazaki T, Suzuki H, Nishiyama A, Ishii N . Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes. Acta Physiol (Oxf). 2018; 225(2):e13190. PMC: 6335176. DOI: 10.1111/apha.13190. View

Cozzolino M, Stucchi A, Rizzo M, Soldati L, Cusi D, Ciceri P . Vitamin D receptor activation and prevention of arterial ageing. Nutr Metab Cardiovasc Dis. 2012; 22(7):547-52. DOI: 10.1016/j.numecd.2012.03.010. View

Qian Y, Guo X, Che L, Guan X, Wu B, Lu R . Klotho Reduces Necroptosis by Targeting Oxidative Stress Involved in Renal Ischemic-Reperfusion Injury. Cell Physiol Biochem. 2018; 45(6):2268-2282. DOI: 10.1159/000488172. View

Janic M, Lunder M, Novakovic S, Skerl P, Sabovic M . Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders". Int J Mol Sci. 2019; 20(8). PMC: 6514706. DOI: 10.3390/ijms20081844. View

Zhang L, Liu T . Clinical implication of alterations in serum Klotho levels in patients with type 2 diabetes mellitus and its associated complications. J Diabetes Complications. 2018; 32(10):922-930. DOI: 10.1016/j.jdiacomp.2018.06.002. View

Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y . Klotho is a target gene of PPAR-gamma. Kidney Int. 2008; 74(6):732-9. DOI: 10.1038/ki.2008.244. View

10.

Navarro-Gonzalez J, Sanchez-Nino M, Donate-Correa J, Martin-Nunez E, Ferri C, Perez-Delgado N . Effects of Pentoxifylline on Soluble Klotho Concentrations and Renal Tubular Cell Expression in Diabetic Kidney Disease. Diabetes Care. 2018; 41(8):1817-1820. DOI: 10.2337/dc18-0078. View

11.

Gu L, Yun-Sun , Tang H, Xu Z . Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway. J Ethnopharmacol. 2020; 281:113548. DOI: 10.1016/j.jep.2020.113548. View

12.

Kuwahara N, Sasaki S, Kobara M, Nakata T, Tatsumi T, Irie H . HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis. Int J Cardiol. 2007; 123(2):84-90. DOI: 10.1016/j.ijcard.2007.02.029. View

13.

Shimizu H, Bolati D, Adijiang A, Adelibieke Y, Muteliefu G, Enomoto A . Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-ĸB. Am J Nephrol. 2011; 33(4):319-24. DOI: 10.1159/000324885. View

14.

Chen Y, Huang C, Duan Z, Xu C, Chen Y . Klotho/FGF23 axis mediates high phosphate-induced vascular calcification in vascular smooth muscle cells via Wnt7b/β-catenin pathway. Kaohsiung J Med Sci. 2019; 35(7):393-400. DOI: 10.1002/kjm2.12072. View

15.

Frank D, Vince J . Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2018; 26(1):99-114. PMC: 6294779. DOI: 10.1038/s41418-018-0212-6. View

16.

Velagapudi C, Bhandari B, Abboud-Werner S, Simone S, Abboud H, Habib S . The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes. J Am Soc Nephrol. 2011; 22(2):262-73. PMC: 3029899. DOI: 10.1681/ASN.2010040352. View

17.

Haussler M, Whitfield G, Kaneko I, Forster R, Saini R, Hsieh J . The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord. 2011; 13(1):57-69. PMC: 3288475. DOI: 10.1007/s11154-011-9199-8. View

18.

Adeli S, Zahmatkesh M, Tavoosidana G, Karimian M, Hassanzadeh G . Simvastatin enhances the hippocampal klotho in a rat model of streptozotocin-induced cognitive decline. Prog Neuropsychopharmacol Biol Psychiatry. 2016; 72:87-94. DOI: 10.1016/j.pnpbp.2016.09.009. View

19.

Yao Y, Wang Y, Zhang Y, Liu C . Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways. Lipids Health Dis. 2017; 16(1):77. PMC: 5390438. DOI: 10.1186/s12944-017-0447-0. View

20.

Tarhani F, Heidari G, Nezami A . Evaluation of α-klotho level in insulin dependent diabetes mellitus (IDDM) children. J Pediatr Endocrinol Metab. 2020; 33(6):761-765. DOI: 10.1515/jpem-2019-0591. View