Abstract

Recent studies demonstrated that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function following AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase 3 (PDE3, cAMP and cGMP activity) and 4 (PDE4, cAMP activity) inhibitors in stimulating MB, primary cultures of renal proximal cells (RPTC) were treated with a panel of inhibitors for 24h and PDE3, but not PDE4 inhibitors, increased FCCP-uncoupled oxygen consumption rate (FCCP-OCR), a marker of MB. Exposure of RPTC to the PDE3 inhibitors, cilostamide and trequinsin, for 24h increased peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mtDNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, while 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTC and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid (FA)-induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.