EET-mediated mechanisms of protection against AKI

• Applicants: Professorin Dr. Duska Dragun (†); Dr. Wolf-Hagen Schunck
• Subject Area: Nephrology
• Term: from 2011 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 152203169

The long-term objective of this project is to identify novel targets for the prevention and treatment of acute kidney injury (AKI). We propose that cytochrome P450 (CYP)-dependent eicosanoids such as 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) play crucial roles in the initial steps of the pathophysiological cascade induced by ischemia-reperfusion (I/R) and eventually leading to AKI. 20-HETE may aggravate the injury by mediating persistent vasoconstriction and stimulating pro-inflammatory and pro-apoptotic pathways, whereas EETs are expected to have an opposite beneficial effect by suppressing these early I/R-induced events. To test these hypotheses, we will use (i) drugs that specifically target the synthesis and action of 20-HETE or EETs and (ii) transgenic and knockout mice with genetically modified capacities of 20-HETE or EET production. The effects of these pharmacological and genetic interventions will be analyzed in terms of I/R-induced renal dysfunction, tubular injury and expression of pro-inflammatory and pro-apoptotic pathways. Complementary studies on hemodynamic changes and key signaling components modulated by the CYP-eicosanoids will be performed in collaboration with Project 3. Finally, we will use a syngeneic rat kidney transplantation model to test the combined utility of 20-HETE-antagonists, novel EET-agonists, and inhibitors of the EET-degrading soluble epoxide hydrolase for improving cold preservation of donor kidneys and promoting early graft function and long-term graft survival.

• DFG Programme: Research Units
• Subproject of: FOR 1368: Hemodynamic Mechanisms of Acute Kidney Injury