COX-2-derived prostaglandins from the macula densa are important modulators of renin expression and renal hemodynamics, while COX-2-derived prostaglandins in the medulla mediate natriuresis and diuresis. There is also increasing evidence that COX-2 metabolites are mediators of renal pathophysiology associated with chronic renal disease. Although COX-2 inhibitors ameliorate renal injury in experimental animal models, these inhibitors can promote thrombotic vascular injury and raise blood pressure, which limits their clinical use in patients with progressive renal disease. Therefore, there remains a need to identify other mechanisms to selectively inhibit the increased renal cortical COX-2 expression and activity seen in renal disease, preferably while sparing medullary COX-2 expression and activity. The dopaminergic system is a crucial intrarenal regulatory system that is responsible for >50% of the net diuresis and natriuresis occurring in response to volume expansion or dietary salt excess. Increasing evidence also indicates that there is abnormal intrarenal dopamine expression and activity in essential hypertension and in diabetes mellitus, but the pathophysiologic consequences have yet to be explored in detail. Our preliminary studies examining the interaction of the intrarenal dopaminergic and COX-2 systems have determined potentially important roles for this axis in renal physiology and pathophysiology. We propose that modulation of renal COX-2 expression and/or activity plays a crucial role in the physiologic functions of intrarenal dopamine and that altered intrarenal dopamine production and activity in both hypertension and diabetes play a significant role in the associated renal pathophysiology, due in part to alterations in COX-2 expression and function. The proposed studies will utilize unique mouse models with selectively altered intrarenal dopamine levels. We propose three specific aims:
Aim 1 will examine the interaction of intrarenal dopaminergic and COX-2 systems in regulation of renal physiology:
Aim 2 will determine the role of the interactions of the intrarenal dopaminergic and COX-2 systems in development and maintenance of hypertension;
and Aim 3 will examine potential roles of these interactions in development of diabetic nephropathy. We predict that these studies will provide important information about whether modulating the intrarenal dopaminergic system could be a potential therapeutic strategy to alter intrarenal COX-2 expression and activity in progressive renal injury.

Public Health Relevance

Hormonal systems intrinsic to the kidney are essential for regulation of blood pressure and salt and water excretion under normal conditions, and dysregulation of these processes in hypertension and diabetes may contribute to progressive kidney injury. The physiologic and pathophysiologic interactions of these systems, the intrarenal dopaminergic system, the renin angiotensin system and the cyclooxygenase-2 system, are the focus of the proposed studies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Mullins, Christopher V
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Vanderbilt University Medical Center
Internal Medicine/Medicine
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United States
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Wang, Xin; Yao, Bing; Wang, Yinqiu et al. (2017) Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy. Diabetes 66:494-504
Zhang, Ming-Zhi; Wang, Xin; Wang, Yinqiu et al. (2017) IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury. Kidney Int 91:375-386
Lim, Beom Jin; Yang, Jae Won; Zou, Jun et al. (2017) Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. Kidney Int 92:1395-1403
Skrypnyk, Nataliya I; Voziyan, Paul; Yang, Haichun et al. (2016) Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury. Am J Physiol Renal Physiol 311:F268-77
Choma, David P; Vanacore, Roberto; Naylor, Helen et al. (2016) Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients. Am J Physiol Renal Physiol 310:F416-25
Zeng, Fenghua; Kloepfer, Lance A; Finney, Charlene et al. (2016) Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion. Am J Physiol Renal Physiol 311:F695-F707
Chiba, Takuto; Skrypnyk, Nataliya I; Skvarca, Lauren Brilli et al. (2016) Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. J Am Soc Nephrol 27:495-508
Chen, Jianchun; Harris, Raymond C (2016) Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney. J Am Soc Nephrol 27:1689-700
Harris, Raymond C; Cheng, Huifang (2016) Telomerase, Autophagy and Acute Kidney Injury. Nephron 134:145-148
Chang, Jian; Vacher, Jean; Yao, Bing et al. (2015) Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis. Oncotarget 6:33500-11

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