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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Tojo, Akihiro; Kinugasa, Satoshi; Fujita, Toshiro et al. (2016) A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats. Diabetes Metab Syndr Obes 9:1-10
Zhang, Gensheng; Wang, Qiaoling; Zhou, Qin et al. (2016) Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway. Kidney Blood Press Res 41:129-38
Wang, Renjun; Huang, Qian; Zhou, Rui et al. (2016) Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail 9:e002261
Huang, Q; Wang, Q; Zhang, S et al. (2016) Increased hydrogen peroxide impairs angiotensin II contractions of afferent arterioles in mice after renal ischaemia-reperfusion injury. Acta Physiol (Oxf) 218:136-45
Cao, Wei; Li, Aiqing; Wang, Liangliang et al. (2015) A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression. J Am Soc Nephrol 26:1619-33
Wang, Cheng; Luo, Zaiming; Kohan, Donald et al. (2015) Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease. Hypertension 65:1055-63
Sato, Yuka; Sato, Waichi; Maruyama, Shoichi et al. (2015) Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids. J Am Soc Nephrol 26:1806-15
Li, Lingli; Feng, Di; Luo, Zaiming et al. (2015) Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress. Hypertension 66:550-6
Carlström, Mattias; Wilcox, Christopher S; Arendshorst, William J (2015) Renal autoregulation in health and disease. Physiol Rev 95:405-511
Wang, Huan; Hong, Ling-Juan; Huang, Ji-Yun et al. (2015) P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy. Cell Res 25:674-90

Showing the most recent 10 out of 107 publications