Elevation of glomerular capillary pressure is a major risk factor for hypertensive renal injury. Ang II hypertension impairs autoregulation and eliminates P2X1 receptor- mediated vasoconstriction, which is critically important for mediating afferent arteriolar autoregulatory behavior. Impaired autoregulation in hypertension coincides with increased renal cytokine production, such as TGF-2 and MCP-1, which may be involved in hypertension-induced renal microvascular dysfunction. Project 2 will determine the role of these cytokines on afferent arteriolar dysfunction in Ang II infused hypertension. Preliminary data indicate that anti-inflammatory treatment prevents afferent arteriolar dysfunction in hypertension. TGF- 2 inhibits autoregulatory responses. Furthermore, MCP-1 inhibition with CCR2 receptor blockade improves autoregulatory efficiency in hypertensive kidneys. These data support the central hypothesis of Project 2 that hypertension initiates intrarenal inflammatory events that result in afferent arteriolar dysfunction and renal injury by impairing P2X1 receptor signaling. Ang II-infused hypertensive rats will be treated with the anti-inflammatory agents, pentosan polysulfate or mycophenolate mofetil, to inhibit inflammatory processes. Experiments will establish the impact of anti-inflammatory treatment on impaired arteriolar autoregulatory behavior, reduced afferent arteriolar reactivity to P2 receptor stimulation, preglomerular vascular smooth muscle Ca2+ signaling mechanisms and expression and function of ROS and intrarenal inflammatory mediators in hypertensive and normotensive rats. These objectives will be addressed in the following specific aims.
Specific aim 1 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar autoregulatory behavior in Ang II-infused hypertensive rats.
Specific aim 2 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar P2X1 receptor reactivity in Ang II-infused hypertensive rats.
Specific aim 3 will test the hypothesis that MCP-1 contributes significantly to the hypertension induced afferent arteriolar dysfunction and impaired Ca2+ signaling mechanisms that occur in Ang II- infused hypertension.
Specific aim 4 will test the hypothesis that hypertension-induced increases in TGF-2 and ROS contribute significantly to the decline in afferent arteriolar function. These studies will provide new mechanistic information linking chronic inflammatory events with suppression of autoregulatory function, impairment of Ca2+ signaling and renal microvascular reactivity to P2X receptor stimulation and they will demonstrate that suppression of inflammatory events leads to improved renal microvascular function and renal protection in hypertension.

Public Health Relevance

This project focuses on determining the mechanisms involved in the autoregulatory and renal microvascular dysfunction that occurs in Ang II hypertension. Our preliminary work suggests a strong link to inflammation and inflammatory mediators playing a causal role in this renal vascular impairment. Understanding the impact of hypertension and inflammation on renal vascular function will provide unique insights capable of reducing hypertensive kidney injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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OH, Youngsuk
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Osmond, David A; Zhang, Shali; Pollock, Jennifer S et al. (2014) Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. Am J Physiol Renal Physiol 306:F619-28
Fellner, Robert C; Cook, Anthony K; O'Connor, Paul M et al. (2014) High-salt diet blunts renal autoregulation by a reactive oxygen species-dependent mechanism. Am J Physiol Renal Physiol 307:F33-40
Guan, Zhengrong; Singletary, Sean T; Cook, Anthony K et al. (2014) Sphingosine-1-phosphate evokes unique segment-specific vasoconstriction of the renal microvasculature. J Am Soc Nephrol 25:1774-85
Giachini, Fernanda R; Leite, Romulo; Osmond, David A et al. (2014) Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats. PLoS One 9:e91890
Guan, Zhengrong; Fellner, Robert C; Van Beusecum, Justin et al. (2014) P2 receptors in renal autoregulation. Curr Vasc Pharmacol 12:818-28
Guan, Zhengrong; Giddens, Matthew I; Osmond, David A et al. (2013) Immunosuppression preserves renal autoregulatory function and microvascular P2X(1) receptor reactivity in ANG II-hypertensive rats. Am J Physiol Renal Physiol 304:F801-7
Kohan, Donald E; Rossi, Noreen F; Inscho, Edward W et al. (2011) Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 91:1-77
Guan, Zhengrong; Inscho, Edward W (2011) Role of adenosine 5'-triphosphate in regulating renal microvascular function and in hypertension. Hypertension 58:333-40
Guan, Zhengrong; Inscho, Edward W (2011) Endothelin and the renal vasculature. Contrib Nephrol 172:35-49
Inscho, Edward W; Cook, Anthony K; Clarke, Andrea et al. (2011) P2X1 receptor-mediated vasoconstriction of afferent arterioles in angiotensin II-infused hypertensive rats fed a high-salt diet. Hypertension 57:780-7

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