Increasing the level of peroxisome proliferator-activated receptor ? coactivator-1? 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? (PGC1?) is one of the main transcriptional regulators of mitochondrial biogenesis and function. We hypothesized that increasing PGC1? expression in podocytes could protect from CKD. We found that PGC1? and mitochondrial transcript levels are lower in podocytes of patients and mouse models with diabetic kidney disease (DKD). To increase PGC1? expression, podocyte-specific inducible PGC1?-transgenic mice were generated by crossing nephrin-rtTA mice with tetO-Ppargc1a animals. Transgene induction resulted in albuminuria and glomerulosclerosis in a dose-dependent manner. Expression of PGC1? in podocytes increased mitochondrial biogenesis and maximal respiratory capacity. PGC1? also shifted podocytes towards fatty acid usage from their baseline glucose preference. RNA sequencing analysis indicated that PGC1? induced podocyte proliferation. Histological lesions of mice with podocyte-specific PGC1? expression resembled collapsing focal segmental glomerular sclerosis. In conclusion, decreased podocyte PGC1? expression and mitochondrial content is a consistent feature of DKD, but excessive PGC1? alters mitochondrial properties and induces podocyte proliferation and dedifferentiation, indicating that there is likely a narrow therapeutic window for PGC1? levels in podocytes.

SUBMITTER: Li SY 

PROVIDER: S-EPMC5518556 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature