Abstract
Uncontrolled diabetes mellitus results in osmotic diuresis. Diabetic patients have lowered nitric oxide (NO) which may exacerbate polyuria. We examined how lack of NO affects the transporters involved in urine concentration in diabetic animals. Diabetes was induced in rats by streptozotocin. Control and diabetic rats were given L-NAME for 3 weeks. Urine osmolality, urine output, and expression of urea and water transporters and the Na-K-2Cl cotransporter were examined. Predictably, diabetic rats presented with polyuria (increased urine volume and decreased urine osmolality). Although metabolic parameters of control rats were unaffected by L-NAME, treated diabetic rats produced 30% less urine and osmolality was restored. UT-A1 and UT-A3 were significantly increased in diabetic rat inner medulla. While L-NAME treatment alone did not alter UT-A1 or UT-A3 abundance, absence of NO prevented the upregulation of both transporters in diabetic rats. Similarly, AQP2 and NKCC2 abundance was increased in diabetic animals however, expression of these transporters were unchanged by L-NAME treatment of diabetes. Increased expression of the concentrating transporters observed in diabetic rats provides a compensatory mechanism to decrease solute loss despite persistent glycosuria. Our studies found that although diabetic-induced glycosylation remained increased, total protein expression was decreased to control levels in diabetic rats treated with L-NAME. While the role of NO in urine concentration remains unclear, lowered NO associated with diabetes may be deleterious to the transporters’ response to the subsequent osmotic diuresis.
Highlights
Diabetes mellitus (DM) is one of the leading causes of death in the United States and is the most common cause of end-stage renal disease (Centers for Disease Control and Prevention, 2008)
ADMINISTRATION OF L-NAME ALTERS METABOLIC PROGRESSION OF DIABETES Age-matched male Sprague Dawley rats from the following experimental groups were individually placed in metabolic cages to monitor physiological changes for 24 h: (1) control rats, (2) rats treated with l-NAME, (3) DM rats, and (4) DM rats treated with l-NAME (Table 1)
NOx levels were lowered 68% in rats treated with l-NAME when compared to control animals, confirming that l-NAME was inhibiting the production of nitric oxide
Summary
Diabetes mellitus (DM) is one of the leading causes of death in the United States and is the most common cause of end-stage renal disease (Centers for Disease Control and Prevention, 2008). Advancing diabetes results in osmotic diuresis and polyuria placing the patient at risk for hypovolemic shock. The ensuing osmotic diuresis and polyuria that occurs with advancing diabetes makes these transporters of particular interest for our studies. Evidence suggests that the decline in renal function associated with advancing diabetes is due to a prolonged state of nitric oxide (NO) deficiency (Huang et al, 2009). NO is generated from nitric oxide synthase (NOS). The decline in NOS activity in the renal medulla is not altered by glucose-dependent osmotic diuresis alone (Lee et al, 2005)
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