Klotho ameliorates cyclosporine A–induced nephropathy via PDLIM2/NF-kB p65 signaling pathway

• Published in: Biochemical and biophysical research communications Vol. 486; no. 2; pp. 451 - 457
• Main Authors: Jin, Meihua, Lv, Pengfei, Chen, Guanyu, Wang, Peng, Zuo, Zhongfu, Ren, Lili, Bi, Jing, Yang, Chul-Woo, Mei, Xifan, Han, Donghe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2017
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenoviridae; Adenoviridae - genetics; Adenoviridae - metabolism; Animals; blood serum; Blood Urea Nitrogen; Cell Line; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; creatinine; Creatinine - blood; Cyclosporine; Cyclosporine A; dose response; epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; excretion; fibrosis; Gene Expression Regulation; gene transfer; genes; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Glucuronidase - genetics; Glucuronidase - metabolism; Glucuronidase - pharmacology; humans; inducible nitric oxide synthase; inflammation; interleukin-12; Interleukin-12 - genetics; Interleukin-12 - metabolism; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; kidney diseases; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Klotho; LIM Domain Proteins - antagonists & inhibitors; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; longevity; luciferase; macrophages; Macrophages - metabolism; Macrophages - pathology; Male; messenger RNA; Mice; Mice, Inbred ICR; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - genetics; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephropathy; NF-kB p65; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; oxidative stress; PDLIM2; quantitative polymerase chain reaction; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; secretion; Signal Transduction; small interfering RNA; transcription factor NF-kappa B; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; urea nitrogen; Cyclosporine A; PDLIM2; Nephropathy; Klotho; NF-kB p65
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2017.03.061

Klotho, an antiaging protein, can extend the lifespan and modulate cellular responses to inflammation and oxidative stress which can ameliorate chronic kidney diseases (CKD). To investigate the molecular mechanism of Klotho on inflammation in cyclosporine A (CsA) induced nephropathy, the mice were transfected with adenovirus mediated Klotho gene and treated with cyclosporine A (CsA; 30 mg/kg/day) for 4 weeks. Also, primary human renal proximal tubule epithelial cells (RPTECs) were treated with soluble Klotho protein and LPS. The results showed that Ad-klotho significantly reduced serum creatinine (Scr) and blood urea nitrogen (BUN) caused by CsA, and significantly increased creatinine clearance. Tubule interstitial fibrosis score (TIF), renal 8-OHdG excretion, macrophage infiltration and MCP-1 were decreased after Ad-klotho gene transfer. In addition, the overexpression of Klotho led to increase in the expression of PDLIM2, decreased in the amount of NF-kB p65, and inhibited the production of inflammatory cytokines (TNFα, IL-6, IL-12) and iNOS. Accordingly, in vitro results showed, Klotho enhanced PDLIM2 expression and reduced NF-kB p65 expression, while PDLIM2 siRNA could block the inhibitory effects of Klotho on expression of NF-kB p65. Secretion of inflammatory cytokines was also inhibited by Klotho treatment, and PDLIM2 siRNA hindered regulatory effects of Klotho on the cytokines. Real-time PCR and Luciferase assay showed that Klotho markedly increased expression of PDLIM2 mRNA and PDLIM2 reporter activity in a dose-dependent manner. These findings suggest that Klotho can modulate inflammation via PDLIM2/NF-kB p65 pathway in CsA-induced nephropathy. •Ad-Klotho gene transfer can ameliorate CsA-induced nephropathy.•Ad-Klotho gene transfer can reduce inflammatory cytokines in CsA-induced nephropathy.•Klotho can regulate PDLIM2/p65 pathway to improve CsA-induced nephropathy.