There is abundant evidence for a urinary concentrating defect in patients with protein or calorie malnutrition and in patients with papillary necrosis due to sickle cell anemia or analgesic nephropathy. These observations suggest that an adequate supply of urea into the renal inner medulla is necessary to concentrate urine maximally. Thus, proper operation of the urinary concentrating mechanism is essential for extracellular volume homeostasis. Understanding the regulation of urea and water transport in the inner medulla could lead to improved therapy for diseases with abnormal urinary concentration or even hypertension. Within the inner medullary collecting duct (IMCD), urea appears to be transported by a specific urea transport protein. Facilitated urea transport is important because it regulates sufficient urea delivery to the deep linner medulla for operation of the concentrating mechanism. The long-term objective of this proposal is to understand the regulation of urea transport and the effect of dietary protein restriction on the concentrating mechanism at the level of collecting duct transport. Using the isolated perfused tubule, a comprehensive study of urea and water transport in rat initial and, terminal IMCDs, will be undertaken. Two hypotheses will be tested: Hypothesis I - Dietary protein restriction reduces concentrating ability by stimulating urea transport in collecting duct segments which do not normally transport urea. Hypothesis II - Dietary protein restriction reduces concentrating ability by altering water transport in collecting duct segments.
Specific Aims 1 - 3 will test the effect of a low-protein (8%) diet on urea transport in the rat initial and terminal IMCD, because a decrease in urea recycling into the deep inner medulla would decrease concentrating ability.
Specific Aims 4 - 5 will test the effect of 8% protein on water transport in the rat terminal and initial IMCD, because an increase in water delivery into the deep inner medulla would decrease concentrating ability.
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