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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098135-03
Application #
8208158
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2010-01-04
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$363,825
Indirect Cost
$116,325
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Van Beusecum, J P; Zhang, S; Cook, A K et al. (2017) Acute toll-like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour. Acta Physiol (Oxf) 221:204-220
Li, Xingsheng; Knight, John; Fargue, Sonia et al. (2016) Metabolism of (13)C5-hydroxyproline in mouse models of Primary Hyperoxaluria and its inhibition by RNAi therapeutics targeting liver glycolate oxidase and hydroxyproline dehydrogenase. Biochim Biophys Acta 1862:233-9
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Van Beusecum, Justin; Inscho, Edward W (2015) Regulation of renal function and blood pressure control by P2 purinoceptors in the kidney. Curr Opin Pharmacol 21:82-8
Pandit, Meghana M; Inscho, Edward W; Zhang, Shali et al. (2015) Flow regulation of endothelin-1 production in the inner medullary collecting duct. Am J Physiol Renal Physiol 308:F541-52
Guan, Zhengrong; VanBeusecum, Justin P; Inscho, Edward W (2015) Endothelin and the renal microcirculation. Semin Nephrol 35:145-55
Fellner, Robert C; Guan, Zhengrong; Cook, Anthony K et al. (2015) Endothelin contributes to blunted renal autoregulation observed with a high-salt diet. Am J Physiol Renal Physiol 309:F687-96
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
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

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