cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury

• Published in: The Journal of pharmacology and experimental therapeutics 2013-12, Vol.347 (3), p.626-634
• Main Authors: Whitaker, Ryan M, Wills, Lauren P, Stallons, L Jay, Schnellmann, Rick G
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Adenosine Triphosphate - metabolism; Animals; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - pharmacology; Drug Discovery and Translational Medicine; Enzyme-Linked Immunosorbent Assay; Female; Folic Acid; Gene Expression - drug effects; Hematinics; Kidney Cortex - drug effects; Kidney Cortex - metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - genetics; Oxygen Consumption - drug effects; Phosphodiesterase 3 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphodiesterase 5 Inhibitors - pharmacology; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Piperazines - pharmacology; Purines - pharmacology; Rabbits; Real-Time Polymerase Chain Reaction; Sildenafil Citrate; Sulfones - pharmacology; Uncoupling Agents - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.113.208017

Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after 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 (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator-activated receptor γ coactivator-1α, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid-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.