PMID- 25999406 OWN - NLM STAT- MEDLINE DCOM- 20160516 LR - 20181113 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 27 IP - 1 DP - 2016 Jan TI - Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor gamma Essential for Resistance to Crescentic GN. PG - 172-88 LID - 10.1681/ASN.2014111080 [doi] AB - Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) may prevent podocyte injury, but the function of glomerular PPARgamma in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARgamma abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARgamma in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Ppargamma gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARgamma gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Ppargamma gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARgamma was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARgamma cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARgamma pathway may be a therapeutic target for RPGN. CI - Copyright (c) 2016 by the American Society of Nephrology. FAU - Henique, Carole AU - Henique C AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; pierre-louis.tharaux@inserm.fr carole.henique@inserm.fr. FAU - Bollee, Guillaume AU - Bollee G AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada; FAU - Lenoir, Olivia AU - Lenoir O AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; FAU - Dhaun, Neeraj AU - Dhaun N AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; British Heart Foundation Centre of Research Excellence (BHF CoRE), Edinburgh, United Kingdom; FAU - Camus, Marine AU - Camus M AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; FAU - Chipont, Anna AU - Chipont A AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; FAU - Flosseau, Kathleen AU - Flosseau K AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; FAU - Mandet, Chantal AU - Mandet C AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; FAU - Yamamoto, Masayuki AU - Yamamoto M AD - Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; FAU - Karras, Alexandre AU - Karras A AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Department of Nephrology and. FAU - Thervet, Eric AU - Thervet E AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Department of Nephrology and. FAU - Bruneval, Patrick AU - Bruneval P AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Department of Pathology, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France; and. FAU - Nochy, Dominique AU - Nochy D AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Department of Pathology, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France; and. FAU - Mesnard, Laurent AU - Mesnard L AD - Unite Mixte de Recherche (UMR) 702, Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France. FAU - Tharaux, Pierre-Louis AU - Tharaux PL AD - Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la Recherche Medicale (INSERM), Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, Paris, France; Department of Nephrology and pierre-louis.tharaux@inserm.fr carole.henique@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150521 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (NF-E2-Related Factor 2) RN - 0 (PPAR gamma) SB - IM MH - Animals MH - Glomerulonephritis/*etiology MH - Male MH - Mice MH - NF-E2-Related Factor 2/*physiology MH - PPAR gamma/*biosynthesis MH - Podocytes/*metabolism PMC - PMC4696572 OTO - NOTNLM OT - focal segmental glomerulosclerosis OT - glomerular disease OT - glomerulonephritis OT - metabolism OT - podocyte OT - renal protection EDAT- 2015/05/23 06:00 MHDA- 2016/05/18 06:00 PMCR- 2017/01/01 CRDT- 2015/05/23 06:00 PHST- 2014/11/06 00:00 [received] PHST- 2015/03/29 00:00 [accepted] PHST- 2015/05/23 06:00 [entrez] PHST- 2015/05/23 06:00 [pubmed] PHST- 2016/05/18 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - ASN.2014111080 [pii] AID - 2014111080 [pii] AID - 10.1681/ASN.2014111080 [doi] PST - ppublish SO - J Am Soc Nephrol. 2016 Jan;27(1):172-88. doi: 10.1681/ASN.2014111080. Epub 2015 May 21.