Dysfunction of the endothelium dependent relaxation factor/nitric oxide (EDRF/NO) in blood vessels accompanies salt sensitive hypertension, diabetes mellitus (DM) and cardiovascular disease. Asymmetric dimethylarginine (ADMA) impairs EDRF/NO either by competing with the NOS substrate, L-arginine for membrane transport via system y+, or by competitive inhibition of NOS. Therefore, ADMA could underlie defective EDRF/NO responses that contribute to cardiovascular disease. However, the normal regulation of ADMA has not been extensively studied. ADMA is metabolized by dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). We have found that DDAH-2 is heavily expressed in the kidney, especially in the macula densa cells and distal nephron. DDAH-1 is heavily expressed in the vascular endothelium and proximal tubules. Our studies show that Angiotensin II upregulate DDAH-2 (and thereby may reduce macula densa ADMA) but downregulates DDAH-1 (and thereby may increase endothelial ADMA). Dietary salt restriction and early insulinopenic DM both impairs EDRF/NO. This defect can be overcome by excess arginine, suggesting that NO may be inhibited by ADMA. Indeed, we have found that salt restriction decreases plasma arginine, yet increases plasma ADMA and impairs the EDRF/NO responses to acetylcholine of isolated mesenteric resistance vessels. In contrast, we have found that DM increases renal DDAH-2 expression, leading to reduced renal ADMA levels. A consequent increase in macula densa NO could block the vasoconstrictive tubuloglomrular feedback (TGF) response and thereby vasodilate the renal afferent arteriole selectively, leading to glomerular hyperfiltration. We propose to test the hypothesis that arginine delivery, transport and metabolism by NOS in the kidneys and microvascular resistance vessels is differentially regulated by DDAH thereby leading to site- and cell-specific generation of ADMA and NO during physiologic adaptations to changes in salt intake and pathophysiologic responses to insulinopenic DM. We have developed a gene silencing strategy targeting DDAH-1 and -2 in the rat to test the specific roles of these isoforms in physiologic studies of EDRF/NO in resistance vessels and TGF in the kidney. The first two aims test the hypothesis that dietary salt restriction limits NO generation in vascular endothelium because of a reduction in plasma arginine concentration and a decrease in DDAH-1 activity in endothelial cells. This could reduce the intracellular arginine: ADMA concentration, thereby inhibiting EDRF/NO. We propose to examine the specific roles of angiotensin and mineralocorticosteroid receptors.
The third aim tests the hypothesis that during early insulinopenic DM downregulation of DDAH-1 in endothelium underlies the defective EDRF/NO that precedes vasculopathy whereas upregulation of DDAH-2 in the macula densa enhances local NO that blocks the tubuloglomerular feedback (TGF) response causing hvperfiltration that precedes nephropathv.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK049870-11
Application #
6868555
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ketchum, Christian J
Project Start
1997-07-01
Project End
2009-11-30
Budget Start
2005-01-05
Budget End
2005-11-30
Support Year
11
Fiscal Year
2005
Total Cost
$364,720
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Zhao, L; Gao, Y; Cao, X et al. (2017) High-salt diet induces outward remodelling of efferent arterioles in mice with reduced renal mass. Acta Physiol (Oxf) 219:652-659
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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
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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
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

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