20-HETE and EETs in pressure natriuresis

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The concept that the kidney plays a dominant role in the long-term control of arterial pressure is based on the pressure-natriuresis. Previous work by our laboratory has indicated that pressure-natriuresis is associated with inhibition of Na+ transport in the proximal tubule and the loop of Henle and identified an important role for elevations in renal medullary blood flow and renal interstitial hydrostatic pressure (RIHP) in signaling this response. However, the mechanism by which elevations in renal perfusion pressure (RPP) and/or RIHP inhibit Na transport is unknown and remains a key unanswered question in hypertension research. Recent studies by our lab and others have revealed that arachidonic acid is primarily metabolized by cytochrome P450 (CYP) enzymes to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) in the proximal tubule and TALH where these compounds regulate Na+ transport. Thus, the present study will examine the hypothesis that elevations in RPP (through changes in RIHP) increase the production of 20-HETE and/or EETs in the proximal and TALH and that these compounds mediate pressure-natriuresis by inhibiting Na+transport in these nephron segments. Aim 1 will determine whether elevations in RPP and RIHP increase the levels of EETs and 20-HETE in renal interstitial fluid and cortical and medullary tissue using in vivo microdialysis and new fluorescent HPLC and LC/MS assays that we developed for measuring EETs and 20-HETE. Aim 2 will examine the effects of acute and chronic blockade of the synthesis or actions of EETs and 20-HETE on pressure natriuresis and Na in the proximal tubule and TALH using in vivo tubular perfusion. These studies will take advantage of novel specific inhibitors of the synthesis and actions of 20-HETE and EETs that we recently developed in collaboration with Dr. Falck and Tashio Pharmaceutical Corp. This aim will also examine whether 20-HETE and EETs mediate the inhibitory effects of elevations in RPP on Na by inhibiting Na+-K in the proximal tubule and TALH or by altering the distribution of Na+ transporters in the apical membranes of these nephron segments. Aim 3 will characterize the effects of elevations in Na on the levels of EETs and 20-HETE in the kidney of salt-sensitive and salt-resistant strains of rats and whether chronic blockade of the formation of 20-HETE and/or EETs blunts pressure-natriuresis and promotes the development of salt-sensitive hypertension in normotensive strains of rats. Aim 4 will determine if reactive oxygen species (ROS) inhibit the synthesis and enhance the degradation of CYP metabolites of AA in the kidney and whether elevations in the renal levels of CYP metabolites of AA contribute to the antihypertensive effects of antioxidant therapy (TEMPOL or vitamin E) in Dahl SS/Mcw rats. This aim will also examine if ROS-induced decreases in the renal levels of 20-HETE and/or EETs contribute to the development of hypertension in salt-resistant strains of rats when renal oxidative stress is elevated by a chronic renal medullary infusion of the superoxide dismutase inhibitor, DETC. Overall, these studies will provide new information regarding the role of CYP metabolites of AA in renal function, pressure-natriuresis and the long-term control of arterial pressure and the potential interactions of this system in mediating some of the deterimental effects of ROS on renal function. This information will likely provide a strong rationale for the clinical development of inducers of the formation of 20-HETE and/or EETs (fibrates) and stable 20-HETE and EET agonists as new theraputic approaches for the treatment of hypertension and renal disease.