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

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 g (PPARg)may prevent podocyte injury, but the function of glomerular PPARg in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARg abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARg in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparg gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARg gain-of-function approach achievedby systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN inmicewith podocyte-specific Pparg gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)deficient mice, loss of podocyte PPARg 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 NRF2PPARg 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 NRF2PPARg pathway may be a therapeutic target for RPGN.