Loss of renal tubular PGC-1α exacerbates diet-induced renal steatosis and age-related urinary sodium excretion in mice. Mus musculus

The kidney has a high energy demand and is dependent on oxidative metabolism for ATP production. Accordingly, the kidney is rich in mitochondria, and mitochondrial dysfunction is a common denominator for several renal diseases. While the mitochondrial master regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is highly expressed in kidney, its role in renal physiology is so far unclear. Here we show that PGC-1α is a central transcriptional regulator of mitochondrial metabolic pathways in the kidney. Moreover we demonstrate that mice with an inducible nephron-specific inactivation of PGC-1α in the kidney display elevated urinary sodium excretion, exacerbated renal steatosis during metabolic stress but normal blood pressure regulation. Overall, PGC-1α seems largely dispensable for basal renal physiology. However, the central role of PGC-1α in renal mitochondrial biogenesis indicates that activation of PGC-1α in the context of renal disorders could be a valid therapeutic strategy to ameliorate renal mitochondrial dysfunction. Overall design: We used microarrays to detect changes in gene expression in whole kidney from mice. Nephron-specific inducible PGC-1alpha knockout (NiPKO) or control mice (CTRL) were fed either a chow diet or a high fat diet (HFD 60 kcal% fat, D12492) for 20 weeks. We used 4 biological replicates for each condition. The samples were: CWT – chow fed CTRL mice; CKO – chow fed NiPKO mice; HWT – HFD fed CTRL mice; HKO – HFD fed NiPKO mice.