The polyuria that occurs in diabetic patients is generally ascribed to an osmotic diuresis. However, we believe that the mechanisms are more complex. The major goal of this proposal is to identify the cellular and molecular mechanisms that contribute to changes in water and solute homeostasis that occur in uncontrolled diabetes. Several metabolic and hormonal abnormalities present in diabetes could contribute to a loss of water and solute or compensatory mechanisms to limit these losses. We plan to evaluate the role of vasopressin and glucocorticoids in regulating medullary transport proteins in diabetic rats since these animals (and humans) have elevated levels of both hormones. We also plan to evaluate the role of angiotensin II since its inhibition is a mainstay of current therapy for diabetes. Identifying these mechanisms could provide novel insights into the compensatory mechanisms that must occur in the kidney that permit patients with uncontrolled type I diabetes to limit the loss of water and solute, thereby limiting volume depletion. HYPOTHESIS - A compensatory response by the kidney to uncontrolled diabetes is to alter the expression and function of medullary transport proteins to limit the loss of water and solute.
Specific Aim 1 : we will test whether expression of urea transporters, aquaporins, and ion channels or transporters are altered in rats with uncontrolled diabetes. Rationale: we have preliminary data showing that 10-20 days of diabetes results in an increase in UT-A1, AQP2, and NKCC2/BSC1 protein abundances.
Specific Aim 2 : we will determine the requirement for vasopressin and/or glucocorticoids in the regulation of urea, water, and sodium transporter proteins in rats with diabetes. Rationale: we have preliminary data showing that UT-A1 and AQP2 protein abundances do not increase in the absence of glucocorticoids or vasopressin.
Specific Aim 3 : we will determine whether blockade of the renin-angiotensin system alters the regulation of urea, water, and sodium transporter proteins in rats with diabetes. Rationale: blockade of the renin-angiotensin system may prevent compensatory changes and worsen water and solute loss.
Specific Aim 4 : we will test whether rapid regulation of urea transporter phosphorylation or function is altered by vasopressin and/or angiotensin II in inner medullary collecting ducts (IMCDs) from rats with diabetes. Rationale: angiotensin II increases phosphorylation of UT-A1 in rat IMCDs through PKC. We have preliminary data showing that PKC inhibition reduces UT-A1 phosphorylation in inner medulla from diabetic rats.
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|Feng, Xiuyan; Huang, Haidong; Yang, Yuan et al. (2009) Caveolin-1 directly interacts with UT-A1 urea transporter: the role of caveolae/lipid rafts in UT-A1 regulation at the cell membrane. Am J Physiol Renal Physiol 296:F1514-20|
|Blount, Mitsi A; Mistry, Abinash C; Frohlich, Otto et al. (2008) Phosphorylation of UT-A1 urea transporter at serines 486 and 499 is important for vasopressin-regulated activity and membrane accumulation. Am J Physiol Renal Physiol 295:F295-9|
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