Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway.
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.
Department of Immunology, Jinzhou Medical University, Jinzhou, Liaoning, China; Key Laboratory of Follicular Development and Reproductive Health, Jinzhou, Liaoning, China.
Meihua
M
Jin
Department of Neurobiology, Jinzhou Medical University, Jinzhou, Liaoning, China.
Pengfei
P
Lv
Department of Anatomy, Jinzhou Medical University, Jinzhou, Liaoning, China.
Guanyu
G
Chen
Department of Neurobiology, Jinzhou Medical University, Jinzhou, Liaoning, China.
Peng
P
Wang
Department of Anatomy, Jinzhou Medical University, Jinzhou, Liaoning, China.
Zhongfu
Z
Zuo
Department of Neurobiology, Jinzhou Medical University, Jinzhou, Liaoning, China.
Lili
L
Ren
Department of Neurobiology, Jinzhou Medical University, Jinzhou, Liaoning, China.
Jing
J
Bi
Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Chul-Woo
CW
Yang
Department of Orthopedics, Jinzhou Medical University, Jinzhou, Liaoning, China. Electronic address: xfmei@outlook.com.
Xifan
X
Mei
Department of Neurobiology, Jinzhou Medical University, Jinzhou, Liaoning, China. Electronic address: handonghe@foxmail.com.
Donghe
D
Han
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D060588:LIM Domain Proteins; C508508:Pdlim2 protein, mouse; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D018664:Interleukin-12; D016572:Cyclosporine; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins
Cyclosporine A; Klotho; NF-kB p65; Nephropathy; PDLIM2