We have shown that the first onset of hyperglycemia in diabetes causes significant renal vasoconstriction and hypertension if it occurs under conditions of chronic nitric oxide (NO) synthesis inhibition. Those deleterious consequences of hyperglycemia are prevented by antioxidant treatment with the superoxide (SO) dismutase mimetic, tempol. The underlying hypothesis is that onset of hyperglycemia in early diabetes induces an angiotensin II-dependent, superoxide-mediated right-shift in the renal pressure-natriuresis relationship, and that nitric oxide is an important counteracting force that prevents hypertension. The experiments in this project will determine the mechanisms for these important interactions by testing the central hypothesis that nitric oxide counteracts angiotensin II-dependent, superoxide-mediated renal vasoconstriction to prevent hypertension during hyperglycemia early in diabetes. Experiments will test this by testing the 3 subhypotheses that: 1. Nitric oxide is required to prevent renal vasoconstriction and hypertension at the onset of diabetes. Our L-NAME, ACh, and glomerular filtration rate (GFR) data support this, but to better implicate NO and define the site(s) for its control of renal function in early diabetes, we will: a. measure renal blood flow 24 hr/d to quantify the changes in resistance and filtration fraction; b. determine the time-, glucose-, and insulin-dependent changes in eNOS and nNOS; c. determine when, and if, vasodilatory prostaglandins assume the vasoprotective role of NO; d. determine the roles of eNOS vs. nNOS using knockout mice and infusion of antagonists. 2. Angiotensin II increases sensitivity to renal vasoconstriction and hypertension during hyperglycemia and is required for those responses to occur. Our evidence supports this role, but to determine Angll's importance independent of L-NAME-induced increases we will determine: a. whether low-sodium intake exacerbates the sensitivity of diabetic rats to NOS inhibition; b. the link between GFR and blood pressure by using decreased kidney mass to control GFR; c. whether onset of diabetes causes hypertension in rats with Angll hypertension; d. the superoxide-independent component of Angll's influence on MAP and renal resistance. 3. Superoxide induces a renal vasoconstrictor and hypertensive influence at the onset of hyperglycemia. We have shown that tempol prevents hypertension in L-NAME-treated diabetic rats, but to more specifically implicate SO, with or w/o NOS blockade, we will determine: a. whether antioxidant treatment can prevent hypertension without decreasing renin secretion; b. whether knockout of SO dismutase-1 (SOD1) exacerbates the hypertensive response; c. whether increased SOD1 in transgenic mice protects against hypertension similar to tempol; d. the role of NADPH oxidase, by measuring p22 phox expression and the effect of apocynin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075625-01
Application #
6719792
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$280,840
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Brands, Michael W; Bell, Tracy D; Rodriquez, Nancy A et al. (2009) Chronic glucose infusion causes sustained increases in tubular sodium reabsorption and renal blood flow in dogs. Am J Physiol Regul Integr Comp Physiol 296:R265-71
Sturgis, LaShon C; Cannon, Joseph G; Schreihofer, Derek A et al. (2009) The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6. Am J Physiol Regul Integr Comp Physiol 297:R1742-8
Brands, Michael W; Labazi, Hicham (2008) Role of glomerular filtration rate in controlling blood pressure early in diabetes. Hypertension 52:188-94
Bell, Tracy D; DiBona, Gerald F; Biemiller, Rachel et al. (2008) Continuously measured renal blood flow does not increase in diabetes if nitric oxide synthesis is blocked. Am J Physiol Renal Physiol 295:F1449-56
Brands, Michael W; Bell, Tracy D; Fleming, Cassandra et al. (2007) Lack of blood pressure salt-sensitivity supports a preglomerular site of action of nitric oxide in Type I diabetic rats. Clin Exp Pharmacol Physiol 34:475-9
Rojas, Modesto; Bell, Tracy D; Sturgis, LaShon C et al. (2006) Blood pressure early in diabetes depends on a balance between glomerular filtration rate and the renin-angiotensin system. Am J Hypertens 19:1249-55
Lee, Dexter L; Sturgis, Lashon C; Labazi, Hicham et al. (2006) Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am J Physiol Heart Circ Physiol 290:H935-40
Bell, Tracy D; DiBona, Gerald F; Wang, Ying et al. (2006) Mechanisms for renal blood flow control early in diabetes as revealed by chronic flow measurement and transfer function analysis. J Am Soc Nephrol 17:2184-92
Lee, Dexter L; Webb, R Clinton; Brands, Michael W (2004) Sympathetic and angiotensin-dependent hypertension during cage-switch stress in mice. Am J Physiol Regul Integr Comp Physiol 287:R1394-8