Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes

Ji Hee Kim, Jian Xie, Kyu Hee Hwang, Yueh Lin Wu, Noelynn Oliver, Minseob Eom, Kyu Sang Park, Nestor Barrezueta, In Deok Kong, R. Paul Fracasso, Chou Long Huang, Seung Kuy Cha

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)140-151
Number of pages12
JournalJournal of the American Society of Nephrology : JASN
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • Klotho
  • podocyte
  • TRPC6

ASJC Scopus subject areas

  • Nephrology

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    Kim, J. H., Xie, J., Hwang, K. H., Wu, Y. L., Oliver, N., Eom, M., Park, K. S., Barrezueta, N., Kong, I. D., Fracasso, R. P., Huang, C. L., & Cha, S. K. (2017). Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes. Journal of the American Society of Nephrology : JASN, 28(1), 140-151. https://doi.org/10.1681/ASN.2015080888