Acute kidney injury (AKI) is a severe pathological state characterized by rapid loss of renal function with high levels of morbidity and mortality. AK is a consequence of a variety of conditions including renal ischemia- reperfusion (I/R) and drug or toxin exposure. With no effective therapeutic options and an array of increasing risk factors, AKI is a growing problem that needs to be addressed to both improve patient care and reduce healthcare costs. The development of new therapies for AKI has been largely unsuccessful, and treatment outcomes from AKI have remained unchanged for several decades. Therefore, the development of new, effective therapies requires the identification of novel molecular targets. Following I/R injury, mitochondrial dysfunction contributes to oxidative stress, persistent energy depletion and impairment of energy dependent repair mechanisms, ultimately leading to end organ damage and failure in a variety of tissues. Our laboratory has demonstrated persistent mitochondrial dysfunction and depletion of mitochondrial proteins following renal I/R injury that correlates with sustained renal tubular dysfunction in these animals. These results indicate that restoration of mitochondrial function may be an effective therapeutic strategy for accelerating recovery from AKI. Mitochondrial biogenesis is the process by which new mitochondria are formed within the cell and serves as the primary mechanism of increasing energy output during pathological times of need. Currently, there are few pharmacological agents that are capable of inducing mitochondrial biogenesis. We tested PDE inhibitors due to the potential role of cAMP in the regulation of peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1 ?), the """"""""master regulator"""""""" of mitochondrial biogenesis. We demonstrated that PDE3, but not PDE4 inhibitors stimulated mitochondrial biogenesis as assessed by increases in FCCP-uncoupled respiration. Additionally, mRNA expression of PGC1- ?, as well as complex I proteins ND6 and NDUFB8 was increased. We hypothesize that PDE3 inhibitors specifically induce mitochondrial biogenesis through PGC-1? and promote recovery from AKI. We believe that CREB phosphorylation by cAMP-activated protein kinase A (PKA) serves as the primary regulatory mechanism for PGC-1? transcriptional upregulation and subsequent mitochondrial biogenesis with PDE3 inhibitors, and that this biogenic response will promote accelerated recovery from I/R-induced AKI. This hypothesis will be addressed through the following Specific Aims: 1) Characterize mitochondrial biogenic and functional changes in vitro in RPTC treated with PDE3 inhibitors, and elucidate the mechanism thereof, 2) Characterize the mitochondrial biogenic and functional changes in mice treated with PDE3 inhibitors and elucidate the mechanism thereof, and 3) Determine the effect of PDE3 inhibitors on the recovery of renal function following I/R injury. Completion of this study may lead to the development of a set of highly effective pharmacological agents for the treatment of AKI. As mitochondrial biogenesis is a ubiquitous process, these agents may prove effective in the treatment of acute injury in other organs including heart, liver and brain.
Acute kidney injury (AKI) is a disease state affecting up to 5% of all long-term hospital patients and contributing to death in 20-50% of these patients, for which there are currently no highly effective therapies. There have been no significant improvements in patient survival from AKI for several decades. This project seeks to examine the mechanism and usefulness of blocking phosphodiesterase 3 in the treatment of AKI, with hope that this unique target will provide a better treatment option for patients with this serious disease.
|Whitaker, Ryan M; Corum, Daniel; Beeson, Craig C et al. (2016) Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases. Annu Rev Pharmacol Toxicol 56:229-49|
|Whitaker, Ryan M; Stallons, L Jay; Kneff, Joshua E et al. (2015) Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury. Kidney Int 88:1336-1344|
|Whitaker, Ryan M; Korrapati, Midhun C; Stallons, Lindsey J et al. (2015) Urinary ATP Synthase Subunit Î² Is a Novel Biomarker of Renal Mitochondrial Dysfunction in Acute Kidney Injury. Toxicol Sci 145:108-17|
|Garrett, Sara M; Whitaker, Ryan M; Beeson, Craig C et al. (2014) Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury. J Pharmacol Exp Ther 350:257-64|
|Stallons, L Jay; Whitaker, Ryan M; Schnellmann, Rick G (2014) Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicol Lett 224:326-32|
|Whitaker, Ryan M; Wills, Lauren P; Stallons, L Jay et al. (2013) cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury. J Pharmacol Exp Ther 347:626-34|