The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1 alpha is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1 alpha levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1 alpha deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1 alpha overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1 alpha activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1 alpha activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1 alpha activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.