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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045688-03
Application #
2144895
Study Section
Physiology Study Section (PHY)
Project Start
1993-01-01
Project End
1996-06-30
Budget Start
1995-01-01
Budget End
1996-06-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Swenson, K L; Sands, J M; Jacobs, J D et al. (1997) Effect of aging on vasopressin and aquaporin responses to dehydration in Fischer 344-brown-Norway F1 rats. Am J Physiol 273:R35-40
Sands, J M; Kokko, J P (1996) Current concepts of the countercurrent multiplication system. Kidney Int Suppl 57:S93-9
Sands, J M; Naruse, M; Jacobs, J D et al. (1996) Changes in aquaporin-2 protein contribute to the urine concentrating defect in rats fed a low-protein diet. J Clin Invest 97:2807-14
Sands, J M; Martial, S; Isozaki, T (1996) Active urea transport in the rat inner medullary collecting duct: functional characterization and initial expression cloning. Kidney Int 49:1611-4
Ashkar, Z M; Martial, S; Isozaki, T et al. (1995) Urea transport in initial IMCD of rats fed a low-protein diet: functional properties and mRNA abundance. Am J Physiol 268:F1218-23
Smith, C P; Lee, W S; Martial, S et al. (1995) Cloning and regulation of expression of the rat kidney urea transporter (rUT2). J Clin Invest 96:1556-63
Tumlin, J A; Hoban, C A; Medford, R M et al. (1994) Expression of Na-K-ATPase alpha- and beta-subunit mRNA and protein isoforms in the rat nephron. Am J Physiol 266:F240-5
Isozaki, T; Gillin, A G; Swanson, C E et al. (1994) Protein restriction sequentially induces new urea transport processes in rat initial IMCD. Am J Physiol 266:F756-61
Lea, J P; Sands, J M; McMahon, S J et al. (1994) Evidence that the inhibition of Na+/K(+)-ATPase activity by FK506 involves calcineurin. Kidney Int 46:647-52
Isozaki, T; Lea, J P; Tumlin, J A et al. (1994) Sodium-dependent net urea transport in rat initial inner medullary collecting ducts. J Clin Invest 94:1513-7

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