Repression of peroxisome proliferation-activated receptor γ coactivator-1α by p53 after kidney injury promotes mitochondrial damage and maladaptive kidney repair.

Abstract

Maladaptive kidney repair after injury is associated with a loss of mitochondrial homeostasis, but the underlying mechanism is largely unknown. Moreover, it remains unclear whether this mitochondrial change contributes to maladaptive kidney repair or the development of chronic kidney problems after injury. Here, we report that the transcriptional coactivator peroxisome proliferation-activated receptor γ coactivator-1α (PGC1α), a master regulator of mitochondrial biogenesis, was persistently downregulated during maladaptive kidney repair after repeated low-dose cisplatin nephrotoxicity or unilateral ischemia/reperfusion injury. Administration of the PGC1α activator ZLN005 after either kidney injury not only preserved mitochondria but also attenuated kidney dysfunction, tubular damage, interstitial fibrosis, and inflammation. PGC1α downregulation in these models was associated with p53 activation. Notably, knockout of p53 from proximal tubules prevented PGC1α downregulation, attenuated chronic kidney pathologies and minimized functional decline. Inhibition of p53 with pifithrin-α, a cell permeable p53 inhibitor, had similar effects. Mechanistically, p53 bound to the PGC1α gene promoter during maladaptive kidney repair and this binding was suppressed by pifithrin-α. Together, our results indicate that p53 is induced during maladaptive kidney repair to repress PGC1α transcriptionally, resulting in mitochondrial dysfunction for the development of chronic kidney problems. Activation of PGC1α and inhibition of p53 may improve kidney repair after injury and prevent the development of chronic kidney problems.