title: Calcineurin (CN) activation promotes apoptosis of glomerular podocytes both in vitro and in vivo.
abstract: To determine the role of Gq signaling and calcineurin (CN) activation in promoting apoptosis of glomerular podocytes, constitutively active Gq [Gq(+)] or CN [CN(+)] proteins were introduced into cultured podocytes using protein transduction by tagging the proteins with the transactivator of transcription peptide. To investigate the role of CN in promoting podocyte apoptosis in vivo, a genetic model of type 1 diabetes mellitus (Akita mice) was treated with the CN inhibitor FK506. In cultured podocytes, Gq(+) stimulated nuclear translocation of nuclear factor of activated T cells (NFAT) family members, activated an NFAT reporter construct, and enhanced podocyte apoptosis in a CN-dependent fashion. CN(+) similarly promoted podocyte apoptosis, and apoptosis induced by either angiotensin II or endothelin-1 was blocked by FK506. Induction of apoptosis required NFAT-induced gene transcription because apoptosis induced by either Gq(+) or CN(+) was blocked by an inhibitor that prevented CN-dependent NFAT activation without affecting CN phosphatase activity. Podocyte apoptosis was mediated, in part, by the NFAT-responsive gene cyclooxygenase 2 (COX2) and prostaglandin E(2) generation because apoptosis induced by Gq(+) was attenuated by either COX2 inhibition or blockade of the Gq-coupled E-series prostaglandins receptor. The findings appeared relevant to podocyte apoptosis in diabetic nephropathy because apoptosis was significantly reduced in Akita mice by treatment with FK506. These data suggest that Gq stimulates CN and promotes podocyte apoptosis both in vitro and in vivo. Apoptosis requires NFAT-dependent gene transcription and is mediated, in part, by CN-dependent COX2 induction, prostaglandin E(2) generation, and autocrine activation of the Gq-coupled E-series prostaglandins receptor.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University, Durham Veterans Affairs Medical Centers, Durham, North Carolina 27710, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Chang
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Paik
authors.forename: Yuping
authors.initials: Y
authors.lastname: Tang
authors.forename: William
authors.initials: W
authors.lastname: Eisner
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spurney
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003720:Densitometry; D015232:Dinoprostone / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494009:Nfatc3 protein, mouse; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C121611:VIVIT peptide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019703:Calcineurin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D015232:Dinoprostone; D016559:Tacrolimus