Afferent arteriolar function and novel small molecules for renal radiation injury

Clement J. Zablocki Va Medical Center, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): Radiation nephropathy occurs after radiation therapies for cancer, and may also occur after accidental or belligerent radiation events. It is thus highly relevant to veterans with cancer and o those who had radiation injury from military occupational exposures. Current treatments are insufficient. We will test epoxyeicosatrienoic acid (EET) analogues as novel mitigators and treatment of radiation nephropathy. Radiation nephropathy causes endothelial injury, results in hypertension, parenchymal cell loss, and renal failure. We have developed epoxyeicosatrienoic acid (EET) analogs/mimetics that have endothelial-protective, anti-hypertensive, and anti-apoptotic actions that will be particularly beneficial in this patient population. We have shown that an EET analog dilates renal arterioles and lowers blood pressure in hypertensive rats and a mouse model of metabolic syndrome. We have also shown that these novel EET analogs protect the kidney from cisplatin-induced nephrotoxicity and hypertensive renal injury. We designed, synthesized, and screened a series of ~50 EET analogs and found two novel EET analogs that act when given orally. Vascular relaxation determined a ~1.5 M EC50 and a maximal response that was ~95% of that of 14,15-EET. The existing gold standard mitigator and treatment for radiation nephropathy is captopril, an angiotensin-converting-enzyme (ACE) inhibitor. Its benefit is incomplete. Better agents are needed for renal and other normal tissue radiation injuries. Our central hypothesis is that EETs have vascular protective activities that wil translate into a novel therapeutic for radiation nephropathy. The overall objective of this application is to determine the contribution of EETs to irradiation induced afferent arteriolar endothelial dysfunction and test the concept that increasing EETs will decrease vascular and kidney injury in an animal model of radiation nephropathy. Our long-term goal is establish orally available EET analogs as clinical treatments for radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury. We will test our central hypothesis by pursuing the following specific aims: Aim 1: Determine the time course of afferent arteriolar dysfunction and regulation of EETs following irradiation We hypothesize that afferent arteriolar dysfunction caused by decreased EETs precedes renal injury in an animal model of radiation nephropathy. Aim 2: Determine EET analogs ability to mitigate and treat radiation-induced renal injury We hypothesize that EET analogs will improve afferent arteriolar function through anti-apoptotic activity, will decrease blood pressure and will mitigate and treat radiation induced renal injury. Achievement of our aims will have an important positive impact because these will be a significant advance towards understanding the time course for and mechanism of renal injury following irradiation. The findings of these studies will be significant because they will advance the development of EET analog therapies for the mitigation and treatment of radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury.