cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

Abstract

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 g coactivator-1a, 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 cGMPspecific 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.

5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists

“…By contrast, we used primary cultures of renal epithelial cells that have differentiated functions and physiologic receptor expression to probe a unique mitochondrial target. Thus, it is possible that agonism of the 5-HT 2A receptor in the kidney by either CP-809,101 or SB-242,084 at the doses used in our studies can result in release of calcium and subsequent increase in cGMP, previously demonstrated to be important for pharmacological induction of renal MB (Whitaker et al, 2013). This hypothesis is supported by evidence that SB-242,084 can act as an agonist for the calciummediated signaling pathway of the 5-HT 2C receptor (Roth, 2006;Neve, 2009).…”

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

“…Mitochondrial dysfunction is commonly observed in acute organ injury of the kidney, heart, and liver (Di Lisa et al, 2007;Havasi and Borkan, 2011;Jaeschke et al, 2012). Recovery of renal structure and function following AKI has been reported to be accelerated through stimulation of MB by agonism of the b 2 -adrenergic receptor or by inhibition of cGMP-selective phosphodiesterases (Whitaker et al, 2013;Jesinkey et al, 2014). Likewise, stimulation of MB via agonism of the 5-HT 1F receptor with LY344864 herein was similarly able to promote accelerated renal recovery in an I/R-induced AKI model.…”

“…Stimulation of MB has been previously reported to accelerate the recovery of renal structure and function after AKI (Whitaker et al, 2013;Jesinkey et al, 2014). We examined the ability of LY344864 to stimulate MB and promote renal recovery in an I/Rinduced AKI model.…”

“…Induction of mitochondrial biogenesis (MB) has been shown to alleviate mitochondrial dysfunction following injury in several pathophysiological model systems Dam et al, 2013;Funk and Schnellmann, 2013;Whitaker et al, 2013). Requiring coordination of both the nuclear and mitochondrial genomes, MB is the synthesis of new mitochondria which is mediated by the master regulator peroxisome proliferator-activated receptor coactivator 1-a (PGC1a) (Scarpulla et al, 2012), and replaces defective or deficient mitochondria and/or supplements existing mitochondria to increase respiratory capacity.…”

“…Interestingly, not all b 2 -adrenoceptor agonists were capable of inducing MB (Peterson et al, 2013). Finally, specific inhibition of phosphodiesterases 3 and 5 increased cGMP to produce MB in renal proximal tubule cells (RPTC) and mice, and accelerated the recovery of renal function following acute kidney injury (Whitaker et al, 2013).…”