There is abundant evidence for loss of weight, negative nitrogen balance and loss of protein stores in patients with chronic (CRF) or acute (ARF) renal failure. These observations suggest that uremia adversely affects protein nutrition. Understanding mechanisms for this effect of uremia could lead to improved therapy for these patients. Few proposed mechanisms explain abnormal protein nutrition in uremia. We found that metabolic acidosis causes increased catabolism of BCAA and protein in isolated muscles of normal rats and could explain all of the increased proteolysis in rats with CRF. Glucocorticoids seemed to play an integral role in this response. We also find that uremia is associated with increased intracellular sodium in muscle and adipocytes and there is evidence for impaired NaK-ATPase and Na,K,C1 cotransporter activities; in thymocytes there is evidence for impaired Na-H exchanger activity in uremia. If these defects occur in other tissues, uremia could impair the ability to regulate intracellular pH and aggravate the catabolic response to acidosis. Using the constant amino acid infusion technique, biochemical techniques and cell transport and NMR techniques, 3 hypotheses will be tested: I-Metabolic acidosis activates BCAA and protein catabolism in vivo and impairs the nutritional responses to a low- protein diet. II-Abnormal protein turnover in acidosis and uremia involve specific proteolytic pathways and affect specific proteins. III-Uremia-induced abnormalities in cation transport impair the regulation of intracellular pH.
Specific Aims 1 -4 will test whether metabolic acidosis activates BCAA and protein catabolism in normal and uremic rats in vivo, impairs the adaptive nutritional responses to a low-protein diet and whether abnormalities can be corrected by feeding leucine or a-ketoisocaproate.
Specific Aims 5 -6 will determine whether acidosis in normal and uremic rats activates the ATP-dependent proteolytic pathway in muscle and which component of muscle protein is affected by the catabolic response to acidosis and uremia.
Specific Aims 7 -10 will determine if uremia impairs the regulation of intracellular pH in muscle and if glucocorticoids and/or mild acidosis produce this abnormality. Finally the mechanism for abnormal regulation will be sought by studying Na transport in nutritionally important tissues from acidotic and uremic rats and properties of Na-H exchange in thymocytes as a nucleated cell model.
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