Impaired regulation of renal blood flow (RBF) is recognized as a critical element in the pathologies of diabetes and metabolic syndrome through effects on glomerular pressure, GFR, and urinary sodium excretion (UNaV). The mechanism for impaired RBF regulation in these conditions is not known. We have evidence for a novel physiological effect of insulin on RBF that may translate to mechanisms for pathophysiological RBF impact. Our data suggest that preventing excess sodium loss after meals is the physiological function of insulin- regulated UNaV. This is not due solely to tubular sodium reabsorption, as the literature would predict. We show that insulin also exerts renal vasoconstrictor tone after meals, possibly via thromboxane (TXA2), that limits the degree of meal-induced renal vasodilation. Impairment, of that physiological function should cause excessive renal vasodilation after meals, causing renal salt wasting and potential long-term implications on the progression of CKD. Exaggeration of this physiological function should cause overt renal vasoconstriction, sodium retention, and hypertension if sustained. Additional data show that blocking the protective role of nitric oxide (NO) enables high-sucrose diet to cause hypertension, which we can prevent by blocking hyperinsulinemia. We will test the central hypothesis that: The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence that limits the degree of meal-induced renal vasodilation. Counterbalancing input from nitric oxide is required to prevent overt renal vasoconstriction and hypertension.
The specific aims will test whether:
Aim 1 : The physiological, sodium-conserving effect of insulin is mediated in part by a post-meal renal vasoconstrictor influence. The experiments will test the hypotheses that: a. Preventing the meal-induced increase in plasma insulin will cause greater and more sustained increases in RBF and greater UNaV than occurs in normal control rats. b. The insulin-dependent renal vasoconstrictor influence requires TXA2. c. Under conditions of background NOS inhibition, glucose bolus will cause overall renal vasoconstriction and amplified sodium retention. d. ENaC mediates the tubular reabsorption component of the acute sodium-conserving effect of insulin.
Aim 2 : Impaired NO synthesis causes insulin-dependent renal vasoconstriction and hypertension during high-sucrose intake. Experiments test the hypotheses that: a. NOS inhibition will enable chronic high-sucrose intake to cause hypertension (DSI telemetry, 24 hr/day). b. Blocking hyperinsulinemia will prevent the hypertensive response to high-sucrose intake. Restoring only intra-renal hyperinsulinemia restores the hypertension response. c. TXA2 synthase inhibition will prevent the hypertensive effect of chronic high-sucrose intake.

Public Health Relevance

Although Insulin is well-known to stimulate renal sodium transport, neither the physiological function of this action, nor direct, cause-effect evidence that it causes hypertension, have been described. We have new evidence for renal blood flow regulation by insulin as a novel mechanism for insulin-regulated urinary sodium excretion. This not only has implications for progression of CKD in diabetes, but these studies also will reveal mechanisms that translate insulin's physiological, sodium-conserving role into a mechanism for chronic hypertension in metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK124303-01
Application #
9945551
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Maric-Bilkan, Christine
Project Start
2020-07-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Augusta University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912