Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes
| Autor: | Chou Long Huang, Minseob Eom, Seung Kuy Cha, Kyu Hee Hwang, Yueh Lin Wu, Kyu Sang Park, Noelynn Oliver, Nestor X. Barrezueta, Ji Hee Kim, Jian Xie, R. Paul Fracasso, In Deok Kong |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty In situ hybridization Biology urologic and male genital diseases TRPC6 Podocyte 03 medical and health sciences Transient receptor potential channel Mice Internal medicine Extracellular medicine TRPC6 Cation Channel Albuminuria Animals Humans Renal Insufficiency Chronic Klotho Klotho Proteins Cells Cultured Glucuronidase TRPC Cation Channels Kidney Podocytes General Medicine female genital diseases and pregnancy complications Proteinuria 030104 developmental biology medicine.anatomical_structure Endocrinology Basic Research Nephrology medicine.symptom |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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