Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes

Klotho is a type-1 membrane protein predominantly produced in the kidney, the extracellular domain of which is secreted into the systemic circulation. Membranous and secreted Klotho protect organs, including the kidney, but whether and how Klotho directly protects the glomerular filter is unknown. H...

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Published in:Journal of the American Society of Nephrology 2017-01, Vol.28 (1), p.140-151
Main Authors: Kim, Ji-Hee, Xie, Jian, Hwang, Kyu-Hee, Wu, Yueh-Lin, Oliver, Noelynn, Eom, Minseob, Park, Kyu-Sang, Barrezueta, Nestor, Kong, In-Deok, Fracasso, R Paul, Huang, Chou-Long, Cha, Seung-Kuy
Format: Article
Language:English
Subjects:
Albuminuria - etiology
Animals
Basic Research
Cells, Cultured
Glucuronidase - physiology
Humans
Klotho Proteins
Mice
Podocytes
Proteinuria - etiology
Renal Insufficiency, Chronic - complications
TRPC Cation Channels - physiology
TRPC6 Cation Channel
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Summary:Klotho is a type-1 membrane protein predominantly produced in the kidney, the extracellular domain of which is secreted into the systemic circulation. Membranous and secreted Klotho protect organs, including the kidney, but whether and how Klotho directly protects the glomerular filter is unknown. Here, we report that secreted Klotho suppressed transient receptor potential channel 6 (TRPC6)-mediated Ca influx in cultured mouse podocytes by inhibiting phosphoinositide 3-kinase-dependent exocytosis of the channel. Furthermore, soluble Klotho reduced ATP-stimulated actin cytoskeletal remodeling and transepithelial albumin leakage in these cells. Overexpression of TRPC6 by gene delivery in mice induced albuminuria, and exogenous administration of Klotho ameliorated the albuminuria. Notably, immunofluorescence and in situ hybridization revealed Klotho expression in podocytes of mouse and human kidney. Heterozygous Klotho-deficient CKD mice had aggravated albuminuria compared with that in wild-type CKD mice with a similar degree of hypertension and reduced clearance function. Finally, disrupting the integrity of glomerular filter by saline infusion-mediated extracellular fluid volume expansion increased urinary Klotho excretion. These results reveal a potential novel function of Klotho in protecting the glomerular filter, and may offer a new therapeutic strategy for treatment of proteinuria.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2015080888