This project will test three hypotheses. Two concern urine inhibitors of crystallization, in humans and our inbred IH rats; the third concerns human Idiopathic Hypercalciuria (IH). Hypothesis 1): Normal urine inhibits crystallization and renal cell attachment of crystals (with Project 4, Toback); we hypothesize that reduced inhibition by whole urine (Specific Aim 1) and by three specific proteins, nephrocalcin (NC), Tamm-Horsfall protein (THP), and Uropontin (UP) (Specific Aim 2), contribute to human calcium nephrolithiasis (NL). Hypothesis 2): In rats inbred for IH (Project 2, Specific Aim 2), some but not all form calcium stones; we hypothesize that reduced inhibition by urine and the three specific proteins promote stones in some of these animals (Specific Aim 3). Planned methods for hypotheses 1 and 2 include assays for inhibition of COM nucleation, growth, aggregation, and crystal attachment to renal cells applied to mixed urine proteins (Specific Aim 1) and the same assays applied to NC, THP and UP purified from human urines (Specific Aim 2) and urine from IH rats (Specific Aim 3). Hypothesis 3): In IH rats, increased Vitamin D receptor mediates intestinal calcium hyperabsorption; we hypothesize that some human IH patients and their families exhibit vitamin D receptor (VDR) abnormalities that cause intestinal calcium hyperabsorption, hypercalciuria and stones, independent of high serum calcitriol levels, and that elevated VDR levels may be inherited. Planned measurements include: 1) VDR levels in circulating monocytes (with Project 1, Favus); 2) response of monocyte VDR to calcitriol and low calcium diet; 3) calcium absorption using oral calcium load and metabolic balance; 4) serum calcitriol, osteocalcin, and PTH levels, and urine calcium excretion, during low calcium diet or oral calcitriol challenge, in monocyte VDR levels; 5) and family studies of patients found to harbor elevated monocyte VDR levels.
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