title: Glucose specifically regulates TRPC6 expression in the podocyte in an AngII-dependent manner.
abstract: Slit diaphragm and podocyte damage is crucial in the pathogenesis of proteinuria in diabetic nephropathy (DNP). Gain-of-function mutations in TRPC6, a slit diaphragm-associated ion channel, cause glomerulosclerosis; TRPC6 expression is increased in acquired glomerular disease. Hyperglycemia and high intrarenal angiotensin II (AngII) levels could contribute to podocyte injury in DNP. We determined whether glucose regulates TRPC6 expression and TRPC6-mediated Ca(2+) influx into the podocyte and whether these effects are AngII dependent. High glucose levels increased TRPC6 mRNA and protein expression in cultured podocytes; however, TRPC1 and TRPC5 mRNA expression was unaltered. AngII and inducing podocyte injury also specifically increased TRPC6 expression. Angiotensin receptor blockade and inhibition of local AngII production through angiotensin-converting enzyme inhibition prevented glucose-mediated increased TRPC6 expression. In addition, high glucose concentration pretreatment enhanced Ca(2+) influx in podocytes, which was prevented by concomitant angiotensin receptor blockade application and TRPC6 knockdown. Studies with a TRPC6 luciferase promoter construct demonstrated a glucose concentration-dependent effect on TRPC6 promoter activity. In vivo, podocyte TRPC6 protein expression was increased in proteinuric streptozotocin-induced diabetic rats. These data suggest that glucose can activate a local renin-angiotensin system in the podocyte, leading to increased TRPC6 expression, which enhances TRPC6-mediated Ca(2+) influx. Regulation of TRPC6 expression could be an important factor in podocyte injury due to chronic hyperglycemia and the antiproteinuric effect of angiotensin receptor blockade or angiotensin-converting enzyme inhibition in DNP.
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Sonneveld
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marijke P A
authors.initials: MP
authors.lastname: Baltissen
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sjoerd A J
authors.initials: SA
authors.lastname: Verkaart
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jo H M
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: tom.nijenhuis@radboudumc.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: Nijenhuis
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000235:genetics; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D000074287:TRPC6 Cation Channel
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C492145:Trpc6 protein, rat; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D005947:Glucose