title: Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.
abstract: 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 γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ 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-PPARγ 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-PPARγ pathway may be a therapeutic target for RPGN.
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; pierre-louis.tharaux@inserm.fr carole.henique@inserm.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Henique
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bollee
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Olivia
authors.initials: O
authors.lastname: Lenoir
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; British Heart Foundation Centre of Research Excellence (BHF CoRE), Edinburgh, United Kingdom;
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Marine
authors.initials: M
authors.lastname: Camus
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Anna
authors.initials: A
authors.lastname: Chipont
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Flosseau
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and.
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Nochy
authors.affiliation: Unité Mixte de Recherche (UMR) 702, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.affiliation: Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology and pierre-louis.tharaux@inserm.fr carole.henique@inserm.fr.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
mesh_terms: D000818:Animals; D005921:Glomerulonephritis / Q000209:etiology*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D047495:PPAR gamma / Q000096:biosynthesis*; D050199:Podocytes / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; D047495:PPAR gamma
keywords: focal segmental glomerulosclerosis; glomerular disease; glomerulonephritis; metabolism; podocyte; renal protection