title: Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes.
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.
authors.affiliation: Departments of Physiology and Global Medical Science.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Departments of Physiology and Global Medical Science.
authors.forename: Kyu-Hee
authors.initials: KH
authors.lastname: Hwang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.|Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; and.
authors.forename: Yueh-Lin
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors.forename: Noelynn
authors.initials: N
authors.lastname: Oliver
authors.affiliation: Department of Pathology, and.
authors.forename: Minseob
authors.initials: M
authors.lastname: Eom
authors.affiliation: Departments of Physiology and Global Medical Science.|Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Park
authors.affiliation: Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors.forename: Nestor
authors.initials: N
authors.lastname: Barrezueta
authors.affiliation: Departments of Physiology and Global Medical Science.|Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: In-Deok
authors.initials: ID
authors.lastname: Kong
authors.affiliation: Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Fracasso
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Chou-Long.Huang@UTSouthwestern.edu skcha@yonsei.ac.kr.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Departments of Physiology and Global Medical Science, Chou-Long.Huang@UTSouthwestern.edu skcha@yonsei.ac.kr.|Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Seung-Kuy
authors.initials: SK
authors.lastname: Cha
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D002478:Cells, Cultured; D005966:Glucuronidase / Q000502:physiology*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D050199:Podocytes; D011507:Proteinuria / Q000209:etiology*; D051436:Renal Insufficiency, Chronic / Q000150:complications; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Klotho; TRPC6; podocyte