Increasing the level of peroxisome proliferator-activated receptor γ coactivator-1α in podocytes results in collapsing glomerulopathy

Abstract

Inherited and acquired mitochondrial defects have been associated with podocyte dysfunction and chronic kidney disease (CKD). Peroxisome proliferator-activated receptor. coactivator-1 alpha (PGC1 alpha) is one of the main transcriptional regulators of mitochondrial biogenesis and function. We hypothesized that increasing PGC1 alpha expression in podocytes could protect from CKD. We found that PGC1 alpha and mitochondrial transcript levels are lower in podocytes of patients and mouse models with diabetic kidney disease (DKD). To increase PGC1 alpha expression, podocyte-specific inducible PGC1 alpha-transgenic mice were generated by crossing nephrin-rtTA mice with tetO-Ppargc1 alpha animals. Transgene induction resulted in albuminuria and glomerulosclerosis in a dose-dependent manner. Expression of PGC1 alpha in podocytes increased mitochondrial biogenesis and maximal respiratory capacity. PGC1 alpha also shifted podocytes towards fatty acid usage from their baseline glucose preference. RNA sequencing analysis indicated that PGC1 alpha induced podocyte proliferation. Histological lesions of mice with podocyte-specific PGC1 alpha expression resembled collapsing focal segmental glomerular sclerosis. In conclusion, decreased podocyte PGC1 alpha expression and mitochondrial content is a consistent feature of DKD, but excessive PGC1 alpha alters mitochondrial properties and induces podocyte proliferation and dedifferentiation, indicating that there is likely a narrow therapeutic window for PGC1 alpha levels in podocytes.