Format

Send to

Choose Destination
J Am Soc Nephrol. 2016 Jan;27(1):172-88. doi: 10.1681/ASN.2014111080. Epub 2015 May 21.

Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.

Author information

1
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.
2
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;
3
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;
4
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;
5
Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;
6
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan;
7
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.
8
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.
9
Unité Mixte de Recherche (UMR) 702, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
10
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.

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.

KEYWORDS:

focal segmental glomerulosclerosis; glomerular disease; glomerulonephritis; metabolism; podocyte; renal protection

PMID:
25999406
PMCID:
PMC4696572
DOI:
10.1681/ASN.2014111080
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center