Vasoconstrictor PGs activating the TP receptor (R) include PGH2, TxA2 and isoprostanes (Iso). NO or peroxynitrite (ONOO), its reaction product with superoxide anion (02"'), can activate cyclooxygenase (COX) whereas O2""and ONOO can inactivate prostacyclin synthase (PGIz-S), activate TxAz synthase and generate Iso, thereby promoting vasoconstrictor PG mechanisms. The specific roles of COX-1 vs. -2, and the diverse agonists of the TP-R and their role in the regulation of microvascular resistance, salt balance and BP remain unclear. This is the focus of this proposal.
Specific Aim I will utilize COX-1 and TP-R gene deleted mice, and specific COX-2 antagonists to investigate the hypothesis that these systems have discrete roles in normal homeostasis by adjusting salt excretion, renal microvascular resistance, tubuloglomerular feedback (TGF) and proximal NaCI reabsorption to stabilize BP and prevent salt sensitivity during changes in salt intake.
Specific Aim II will investigate the hypothesis that neuronal nitric oxide synthase (nNOS)- derived NO generated during macula densa (MD) solute reabsorption activates COX-2 dependent signaling pathway from the MD that regulates afferent arteriolar tone via release of PGH2. PGH2 can be metabolized to vasodilator PG's that limit vasoconstrictor TGF responses, but during Ang II action, PGI2-S is blocked, and PGH2, Iso and TxA2 activate TP-R-dependent enhancement of TGF, thereby assisting in salt and volume preservation.
Specific Aim III will investigate the hypothesis that a COX- and TP-R-dependent process enhances vasoconstriction to Ang II and diminishes vasodUation to acetylcholine of the renal afferent arteriole of mice undergoing an Ang II slow pressor response. These studies are focused on the roles of COX-1 vs. -2, and TP-R in mediating renal mechanism of homeostasis and their dysregulation during Ang II hypertension.
|Wang, Dan; Wang, Cheng; Wu, Xie et al. (2014) Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats: roles of oxidative stress and perivascular adipose tissue. Hypertension 63:1063-9|
|Tao, Rong-Rong; Wang, Huan; Hong, Ling-Juan et al. (2014) Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo. Antioxid Redox Signal 21:1-16|
|Araujo, Magali; Wilcox, Christopher S (2014) Oxidative stress in hypertension: role of the kidney. Antioxid Redox Signal 20:74-101|
|Huang, Ji-Yun; Li, Li-Tao; Wang, Huan et al. (2014) In vivo two-photon fluorescence microscopy reveals disturbed cerebral capillary blood flow and increased susceptibility to ischemic insults in diabetic mice. CNS Neurosci Ther 20:816-22|
|Wilcox, Christopher S; Palm, Fredrik; Welch, William J (2013) Renal oxygenation and function of the rat kidney: effects of inspired oxygen and preglomerular oxygen shunting. Adv Exp Med Biol 765:329-34|
|Persson, Malou Friederich; Welch, William J; Wilcox, Christopher S et al. (2013) Kidney function after in vivo gene silencing of uncoupling protein-2 in streptozotocin-induced diabetic rats. Adv Exp Med Biol 765:217-23|
|Lai, En Yin; Solis, Glenn; Luo, Zaiming et al. (2012) p47(phox) is required for afferent arteriolar contractile responses to angiotensin II and perfusion pressure in mice. Hypertension 59:415-20|
|Wilcox, Christopher S (2012) Asymmetric dimethylarginine and reactive oxygen species: unwelcome twin visitors to the cardiovascular and kidney disease tables. Hypertension 59:375-81|
|Lai, En Yin; Wellstein, Anton; Welch, William J et al. (2011) Superoxide modulates myogenic contractions of mouse afferent arterioles. Hypertension 58:650-6|
|Khawaja, Zeeshan; Wilcox, Christopher S (2011) An overview of candesartan in clinical practice. Expert Rev Cardiovasc Ther 9:975-82|
Showing the most recent 10 out of 91 publications