title: Gq signaling causes glomerular injury by activating TRPC6.
abstract: Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent TRPC6 activation underlies glomerular diseases. Here, we developed a murine model in which a constitutively active Gq α subunit (Gq(Q209L), referred to herein as GqQ>L) is specifically expressed in podocytes and examined the effects of this mutation in response to puromycin aminonucleoside (PAN) nephrosis. We found that compared with control animals, animals expressing GqQ>L exhibited robust albuminuria, structural features of FSGS, and reduced numbers of glomerular podocytes. Gq activation stimulated calcineurin (CN) activity, resulting in CN-dependent upregulation of TRPC6 in murine kidneys. Deletion of TRPC6 in GqQ>L-expressing mice prevented FSGS development and inhibited both tubular damage and podocyte loss induced by PAN nephrosis. Similarly, administration of the CN inhibitor FK506 reduced proteinuria and tubular injury but had more modest effects on glomerular pathology and podocyte numbers in animals with constitutive Gq activation. Moreover, these Gq-dependent effects on podocyte injury were generalizable to diabetic kidney disease, as expression of GqQ>L promoted albuminuria, mesangial expansion, and increased glomerular basement membrane width in diabetic mice. Together, these results suggest that targeting Gq/TRPC6 signaling may have therapeutic benefits for the treatment of glomerular diseases.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Grant
authors.initials: G
authors.lastname: Jirka
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
authors.forename: Anne F
authors.initials: AF
authors.lastname: Buckley
authors.forename: Jose A
authors.initials: JA
authors.lastname: Gomez
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fields
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spurney
mesh_terms: D000419:Albuminuria / Q000139:chemically induced; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D017930:Genes, Reporter; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism; D017354:Point Mutation; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D050778:NFATC Transcription Factors; D011993:Recombinant Fusion Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D011692:Puromycin Aminonucleoside; D019703:Calcineurin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D016559:Tacrolimus
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