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  1. T. Abi Antoun,
  2. J. M. Sands,
  3. J. D. Klein
  1. Emory University School of Medicine, Renal Division, Atlanta, GA


Diabetes is the leading cause of ESRD worldwide. Early manifestations of diabetic renal disease include increased urea excretion, polyuria, and an impaired urine-concentrating ability. Studying the changes that occur at the level of the renal medulla when exposed to the hyperglycemic high-corticosterone milieu of diabetes may help us understand the volume changes that occur early in diabetes, particularly in type I diabetes. UT-A1 is a urea transporter that has been shown to play a critical role in water homeostasis. UT-A1 protein expression is regulated by many hormones including vasopressin, mineralocorticoids, and glucocorticoids. During uncontrolled diabetes, the UT-A1 transporter in the renal medulla decreases initially (at 3-5 days) then increases after 10-21 days in an attempt to restore concentrating ability. A previous study showed that the early decrease in UT-A1 in the renal medulla was prevented in adrenalectomized diabetic rats but restored with the administration of exogenous corticosteroids. In this study we attempt to define the roles of both corticosteroids and mineralocorticoids after a longer period of diabetes (> 10 days). Adrenalectomized (ADX) rats were randomized into 3 groups; one received aldosterone replacement via mini-pump, one received daily dexamethazone injections for 14 days, and one group received no steroid replacement. Three days after replacement was initiated, half the rats in each group were injected with streptozocin to induce diabetes (DM). We compared UT-A1 and AQP2 protein expression in ADX animals, ADX diabetic animals (ADX + DM), and (ADX + DM) animals receiving exogenous mineralocorticoids or glucocorticoids. At 10 days of uncontrolled diabetes, UT-A1 protein expression was unchanged in ADX diabetic rats as compared to ADX nondiabetic rats. In intact animals, UT-A1 is dramatically increased at 10 days of diabetes. When diabetic ADX rats received dexamethasone replacement, UT-A1 protein was decreased significantly in the inner medullary (IM) tip (43 6 2%) but not in the inner medullary base. Similarly, ADX + DM rats receiving aldosterone showed a significant decrease (40 6 2%) in the level of UT-A1 in the IM tip. AQP2 was unchanged in diabetes with or without steroid replacement in ADX rats. We conclude that (1) adrenal steroids are essential in modulating the delayed UT-A1 response to diabetes; (2) both mineralocorticoids and glucocorticoids cause a significant down-regulation of UT-A1 in diabetic rats; and (3) further work is required to understand the increase in UT-A1 observed as a late compensatory reaction to the polyuria of diabetes.

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