title: Vitamin D down-regulates TRPC6 expression in podocyte injury and proteinuric glomerular disease.
abstract: The transient receptor potential cation channel C6 (TRPC6) is a slit diaphragm protein expressed by podocytes. TRPC6 gain-of-function mutations cause autosomal dominant focal segmental glomerulosclerosis. In acquired proteinuric renal disease, glomerular TRPC6 expression is increased. We previously demonstrated that acquired increased TRPC6 expression is ameliorated by antiproteinuric angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Vitamin D also has an antiproteinuric effect. We hypothesized that vitamin D reduces proteinuria by affecting TRPC6 expression in podocytes. Adriamycin-induced nephropathy increased TRPC6 mRNA and protein expression and induced proteinuria in rats. Treatment with 1,25-dihydroxyvitamin D3 (1,25-D3) normalized TRPC6 expression and reduced proteinuria. In vitro, podocyte injury induced by adriamycin exposure in cultured podocytes increased TRPC6 expression. Treatment of injured podocytes with 1,25-D3 dose dependently reduced adriamycin-induced TRPC6 expression. Chromatin immunoprecipitation analysis demonstrated that the vitamin D receptor directly binds to the TRPC6 promoter. Moreover, 1,25-D3 reduced TRPC6 promoter activity in a luciferase reporter assay. In 1,25-D3-deficient 25-hydroxy-1α-hydroxylase knockout mice, TRPC6 expression was increased, accompanied by podocyte foot process effacement and proteinuria. 1,25-D3 supplementation normalized TRPC6 expression, podocyte morphology, and proteinuria in these mice. These results demonstrate that vitamin D down-regulates the enhanced TRPC6 expression in in vivo and in vitro podocyte injury, possibly through a direct effect on TRPC6 promoter activity. This TRPC6 down-regulation could contribute to the antiproteinuric effect of vitamin D.
authors: Department of Nephrology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors: Ramon
authors: R
authors: Sonneveld
authors: Silvia
authors: S
authors: Ferrè
authors: Joost G J
authors: JG
authors: Hoenderop
authors: Henry B
authors: HB
authors: Dijkman
authors: Jo H M
authors: JH
authors: Berden
authors: René J M
authors: RJ
authors: Bindels
authors: Jack F M
authors: JF
authors: Wetzels
authors: Johan
authors: J
authors: van der Vlag
authors: Tom
authors: T
authors: Nijenhuis
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000235:genetics / Q000473:pathology; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011507:Proteinuria / Q000150:complications / Q000235:genetics / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase