Renal tubular 20-HETE and EETs on sodium retention in

Project: Research project

Project Details

Description

This is a proposal to investigate the contribution of renal tubular cytochrome P450-derived eicosanoids, 20-HETE
and EETs, to sodium retention in male rats fed the high-fat (HF) diet, which is an accepted model for obesity-induced
hypertension. 20-HETE and EETs have been shown to affect vascular tone and tubular sodium transport in vitro, as
well as renal function and blood pressure in vivo. Preliminary studies demonstrate that renal 20-HETE and EET
production and the enzymes CYP4A1, CYP4A8, and 2C23, which catalyze this production, are significantly decreased
in renal microsomes after rats have been fed the HF diet for 10 weeks. The down-regulation of eicosanoid production
occurs in the proximal tubules, but not in the renal microvessels. Moreover, the HF diet results in sodium retention and
hypertension, and is associated with down-regulation of peroxisome proliferator-activated receptor a (PPARa).
Furthermore, clofibrate, a selective CYP4A inducer, decreases sodium retention in male rats fed the HF diet. Based on
these findings, the underlying hypothesis is that the HF diet decreases 20-HETE (through PPARa pathway) and EET
production, which may increase the expression of sodium-transporter proteins or modulate their activity, and
consequently causes sodium retention and hypertension. The Specific Aims in this proposal are to test the hypothesis
that: (1) selective induction of tubular 20-HETE and EETproduction can attenuate obesity-induced hypertension by
reducing sodium retention and altering renal function;(2) adenoviral-mediated tubular overexpression of CYP4A and
CYP2C23 can attenuate obesity-induced hypertension by reducing sodium retention and altering renal function;(3) 20-
HETE and EETs can modulate tubular Na+-K+-ATPase and regulate the expression of NHE-3, ROMK, and ENaC and
contribute to sodium retention in HF rats;and (4) activation of PPARa contributes to up-regulation of tubular 20-HETE
production in vitro and in HF rats. These proposed studies will elucidate the role of renal tubular 20-HETE and EETs
in regulating sodium retention in obese HF rats and provide important new information regarding the role of these
eicosanoids in obesity-induced hypertension.
StatusNot started

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