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.
Radiation damage to kidneys and other normal tissue radiation injuries may occur after radiotherapy for cancer or after accidental or belligerent radiation exposures. Treatments for these injuries are limited. We will develop epoxyeicosatrienoic acid (EET) analogs to solve this problem. We have already shown that EETs attenuate kidney damage from hypertension and cis-platinum chemotherapy. We will test EETs in a model of radiation kidney injury, as treatment and as mitigation, and determine the mechanism of those effects. These studies will lead to improved therapies for radiation injury to kidneys and for other normal tissue radiation injuries.
|Yeboah, Michael M; Hye Khan, Md Abdul; Chesnik, Marla A et al. (2018) Role of the cytochrome P-450/ epoxyeicosatrienoic acids pathway in the pathogenesis of renal dysfunction in cirrhosis. Nephrol Dial Transplant 33:1333-1343|
|Skibba, Melissa; Hye Khan, Md Abdul; Kolb, Lauren L et al. (2017) Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition. Front Pharmacol 8:406|
|Hye Khan, Md Abdul; Fish, Brian; Wahl, Geneva et al. (2016) Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. Clin Sci (Lond) 130:587-99|
|Imig, John D; Hye Khan, Md Abdul; Sharma, Amit et al. (2016) Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites. Am J Physiol Heart Circ Physiol 310:H1695-701|
|Finkel, Kevin W; Cohen, Eric P; Shirali, Anushree et al. (2016) Paraprotein-Related Kidney Disease: Evaluation and Treatment of Myeloma Cast Nephropathy. Clin J Am Soc Nephrol 11:2273-2279|
|Cohen, Eric P; Krzesinski, Jean-Marie; Launay-Vacher, Vincent et al. (2015) Onco-nephrology: Core Curriculum 2015. Am J Kidney Dis 66:869-83|