Major Research Areas:
Kidney Diseases, Cardiovascular Diseases, and Diabetes
The Imig laboratory is dedicated to understanding the mechanisms by which certain fatty acids “eicosanoids” influence kidney and cardiovascular function. Research in the laboratory focuses on kidney and blood vessel function in normal and disease states. We have developed novel eicosanoid-based drugs to treat diseases including hypertension, stroke, heart attacks, diabetes, and kidney diseases. These novel drugs have tremendous potential as a therapy for cardiovascular and kidney diseases.
1. Hypertension, Diabetes, & Metabolic Syndrome
Obesity, hypertension, and type 2 diabetes are major contributing factors to the increase in the number of patients that have cardiovascular events and end-organ damage. Metabolic syndrome is a serious health problem worldwide that has two major underlying causes, abdominal obesity and insulin resistance that clusters with other cardiovascular risk factors. Endothelial dysfunction, inflammation, oxidative stress, and insulin resistance are interrelated and increase the risk for cardiovascular events and end-organ damage in hypertension, diabetes, and metabolic syndrome. Moreover, eicosanoids are altered in these diseases and contribute to endothelial function, inflammation, oxidative stress, and insulin resistance. In particular, cyclooxygenase (COX), epoxygenase, and soluble epoxide hydrolase (sEH) metabolites are altered in disease states and contribute to the progression of disease processes. We have identified a distinct synergy between COX-2 and sEH inhibitors on the eicosanoid metabolome. This finding resulted in the development and synthesis of COX-2/sEH inhibitors that demonstrate great promise as a novel therapeutic approach for treating hypertension, diabetes, and metabolic syndrome. The goals of this project will identify novel ways to therapeutically target the eicosanoid metabolome for improving cardiovascular, renal, and pancreatic function in hypertension, diabetes, and metabolic syndrome.
2. Chronic Kidney Disease (CKD)
CKD from any cause is a serious public health problem; an estimated 33 million Americans have kidney disease. Hypertension, obesity, diabetes, infections, and genetic disease can lead to CKD. Other at risk groups include veterans and first-responders exposed to radiation, either on the battlefield, from terrorist events, or as a result of industrial accidents; these people risk developing radiation nephropathy and ultimately CKD. CKD also occurs in 15% of hematopoietic stem cell transplant (HSCT) patients, and has been clearly linked to irradiation at the time of the HSCT. HSCT is increasingly used worldwide for the treatment of cancer, and over 50,000 people per year now undergo HSCT. Long-term survival after HSCT is now near 50%, which means that more people will have late effects, which include CKD. CKD due to radiation also occurs after radionuclide therapy for cancer. Our laboratory has identified and developed epoxyeicosatrienoic acid (EET) analogs that show promise as a novel therapeutic approach for CKD. EET analogs have anti-inflammatory, anti-apoptotic, and anti-oxidative activities that will translate into a novel therapeutic for CKD. Consequently, we will test EET analogs as a new and better treatment for CKD.
3. Acute Kidney Injury (AKI)
Acute kidney injury (AKI), also known as, nephrotoxicity, occurs after exposure to drugs, other medical procedures, or exogenous toxins. The mortality rate for AKI patients is 30-60% and 20-30% of the survivors of AKI will develop CKD. There are limited options for treating AKI and these options currently include fluid and blood pressure management via drugs and intravenous fluids or hemodialysis. EETs have biological actions that implicate them as important contributors to kidney function. Over the past decade it has become increasingly apparent that EETs have a myriad of kidney actions and the overwhelming majority of these biological actions are kidney protective. Our innovation is based on the expected outcome that EET analogs have unique kidney actions that make them a novel target for developing treatments to prevent and treat AKI. Recent studies have demonstrated that EET analogs prevent AKI and renal damage that occurs with the anti-cancer drug cisplatin. This research project will identify novel ways to therapeutically target EETs for treating AKI.
Imig JD, Elmarakby A, Nithipatikom K, Wei S, Capdevila JH, Tuniki VR, Sangra B, Anjaiah S, Manthati VL, Reddy DS, Falck JR. Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions. Frontiers in Vascular Physiology 1:157, 2010. doi: 10.3389/fphys.2010.00157. PMID: 21423396 / PMCID: PMC3059925 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059925/
Luria A, Bettaieb A, Xi Y, Shieh GJ, Liu HC, Inoue H, Tsai HJ, Imig JD, Haj FG, Hammock BD. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance induced by high fat diet. Proc Natl Acad Sci USA 108:9038-9043, 2011 PMID: 21571638 / PMCID: PMC3107315 http://www.pnas.org/content/108/22/9038.long
Elmarakby AA, Faulkner J, Al-Shabrawey M, Wang MH, Maddipati KR, Imig JD. Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced diabetes. Am J Physiol Regul Integr Comp Physiol 301:R1307-R1317, 2011. PMID: 21832210 / PMCID: PMC3213948 http://ajpregu.physiology.org/content/301/5/R1307.long
Imig JD. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiological Reviews 92:101-130, 2012. PMID: 22298653 http://physrev.physiology.org/content/92/1/101.long
Imig JD, Walsh KA, Khan MAH, Nagasawa T, Cherian-Shaw M, Shaw SM, Hammock BD. Soluble epoxide hydrolase inhibition and PPARγ agonist improve vascular function and decrease renal injury in hypertensive obese rats. Exp Biol Med 237:1402-1412, 2012. PMID: 23354399 / PMCID: PMC3613242 http://ebm.sagepub.com/content/237/12/1402.long
Khan MAH, Liu J, Kumar G, Skapek SX, Falck JR, Imig JD. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. FASEB J (in press) PMID: 23603837 http://www.fasebj.org/content/early/2013/04/18/fj.12-218040.long