title: Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease.
abstract: Gain-of-function mutations in the calcium channel TRPC6 lead to autosomal dominant focal segmental glomerulosclerosis and podocyte expression of TRPC6 is increased in some acquired human glomerular diseases, particularly in membranous nephropathy. These observations led to the hypothesis that TRPC6 overactivation is deleterious to podocytes through pathological calcium signaling, both in genetic and acquired diseases. Here, we show that the effects of TRPC6 on podocyte function are context-dependent. Overexpression of TRPC6 alone did not directly affect podocyte morphology and cytoskeletal structure. Unexpectedly, however, overexpression of TRPC6 protected podocytes from complement-mediated injury, whereas genetic or pharmacological TRPC6 inactivation increased podocyte susceptibility to complement. Mechanistically, this effect was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation. Podocyte-specific TRPC6 transgenic mice showed stronger CaMKII activation, reduced podocyte foot process effacement and reduced levels of proteinuria during nephrotoxic serum nephritis, whereas TRPC6 null mice exhibited reduced CaMKII activation and higher levels of proteinuria compared with wild type littermates. Human membranous nephropathy biopsy samples showed podocyte staining for active CaMKII, which correlated with the degree of TRPC6 expression. Together, these data suggest a dual and context dependent role of TRPC6 in podocytes where acute activation protects from complement-mediated damage, but chronic overactivation leads to focal segmental glomerulosclerosis.
authors.affiliation: From the Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Kistler
authors.forename: Geetika
authors.initials: G
authors.lastname: Singh
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Fernandez
authors.forename: Changkyu
authors.initials: C
authors.lastname: Gu
authors.forename: Cory
authors.initials: C
authors.lastname: Wilson
authors.forename: Sandeep Kumar
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Stuart
authors.initials: S
authors.lastname: Dryer
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.forename: Amit K
authors.initials: AK
authors.lastname: Dinda
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D015433:Glomerulonephritis, Membranous / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D003165:Complement System Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; Calcium Signaling; Complement; Kidney; Membranous Nephropathy; Nephrotoxic Serum Nephritis; Podocytes; TRP Channels; TRPC6