Project 5: EET-mediated mechanisms of protection against acute kidney injury
Our long-term objective is to develop novel strategies for the prevention of acute kidney injury (AKI) based on a better understanding of intrinsic renoprotective mechanisms. During the first funding period, we established opposing roles of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) in ischemia/reperfusion (I/R)-induced AKI. 20-HETE aggravated the injury by mediating persistent vasoconstriction and stimulating pro-inflammatory and pro-apoptotic pathways, whereas EETs acted beneficially by suppressing these early I/R-induced events. We will now focus on the role of these cytochrome P450 (CYP)-dependent eicosanoids in ischemic preconditioning (IPC), a highly potent intrinsic mechanism that may provide clinically relevant tools for protecting the kidney in settings such as cardiac surgery. We hypothesize that EETs serve as mediators of IPC, whereas 20-HETE acts as an inhibitor of IPC-induced protective pathways. To test these hypotheses, we will use pharmacological interventions and genetic approaches blocking or enhancing the action of EETs and 20-HETE during IPC in male mice. The effects of these measures on subsequently induced renal I/R injury (I/RI) will be characterized by determining changes in renal function, tubular damage, apoptosis and inflammation. Complementary studies on renal perfusion and oxygenation - in accord with the unifying hypothesis - as well as IPC- and EET-mediated protective signaling will be performed in collaboration with other partners (Projects 2, 3, 6, and 9) of Research unit 1368. The results may establish improved protocols for the prevention of AKI by combining IPC with pharmacological interventions that modulate the CYP-eicosanoid pathway.