Klotho retards renal fibrosis through targeting mitochondrial dysfunction and cellular senescence in renal tubular cells

• Published in: Physiological reports Vol. 9; no. 2; pp. e14696 - n/a
• Main Authors: Miao, Jinhua, Huang, Jiewu, Luo, Congwei, Ye, Huiyun, Ling, Xian, Wu, Qinyu, Shen, Weiwei, Zhou, Lili
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2021; John Wiley and Sons Inc; Wiley
• Subjects: Aging; Animals; Antibodies; Biotechnology; Catenin; Cell culture; Cellular Senescence - drug effects; Clear cell-type renal cell carcinoma; Creatinine; Disease Models, Animal; Ectopic expression; Epithelial cells; Fibrosis; Humans; Ischemia; Kidney diseases; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidneys; Klotho; Klotho protein; Klotho Proteins - administration & dosage; Klotho Proteins - metabolism; Laboratories; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; mitochondrial dysfunction; Original Research; Physiology; Primary Cell Culture; Proteins; Reactive oxygen species; renal fibrosis; Renal function; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Senescence; Wnt protein; Wnt Signaling Pathway - drug effects; Wnt/β‐catenin; Beijing China; United States > US; China; senescence; mitochondrial dysfunction; Klotho; renal fibrosis; Wnt/β-catenin
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.14696

Chronic kidney disease (CKD) has a high prevalence worldwide and is an intricate issue to whole medical society. Renal fibrosis is the common pathological feature for various kinds of CKD. As an anti‐aging protein, Klotho is predominantly expressed in renal tubular epithelial cells. Reports show Klotho could retard age‐related renal fibrosis. Mitochondrial dysfunction plays an important role in cellular senescence. However, the role of Klotho in mitochondrial dysfunction in CKD has not yet been determined. In this study, we treated unilateral ischemia‐reperfusion (UIRI) mice and cultured human renal tubular epithelial cells (HKC‐8) with Klotho. We assessed renal fibrosis, cellular senescence, and Wnt/β‐catenin signaling. We also focused on mitochondrial function assessment. In UIRI mice, ectopic expression of Klotho greatly retarded fibrotic lesions and the activation of Wnt/β‐catenin signaling. Interestingly, Klotho significantly preserved mitochondrial mass, inhibited mitochondrial reactive oxygen species (ROS) production and restored the expression of mitochondrial respiration chain complex subunits. Consequently, Klotho restrained cellular senescence. In HKC‐8 cells, Klotho significantly inhibited Wnt1‐ and Wnt9a‐induced mitochondrial injury, cellular senescence, and fibrotic lesions. These results suggest Klotho has a protective role in renal function through targeted protection on mitochondria. This further broads the understanding of the beneficial efficacies of Klotho in CKD. Our studies suggest Klotho has a protective role in renal function through targeted protection on mitochondria. This further broads the understanding of the beneficial efficacies of Klotho in CKD.