RENAL METABOLISM OF INSULIN AND TYROSINE: STUDIES IN THE ISOLATED PERFUSED RAT KIDNEY
Abstract
Insulin and tyrosine metabolism were studied using the isolated perfused rat kidney to test the following hypotheses: (1) Acute renal failure (ARF) will decrease renal insulin metabolism and that various forms of ARF will affect renal insulin clearance differently. (2) The kidney is a source of urinary p-tyramine and p-tyramine production is regulated by perfusate tyrosine concentrations. The effect of acute renal failure on insulin metabolism was determined in Sprague Dawley rat kidneys following warm ischemia (WI) and uranyl nitrate (UN) toxicity. The effect of acute renal failure on insulin metabolism in Wistar rat kidneys was studied in ureter ligated (UL), warm ischemic, uranyl nitrate-treated, and non-filtering (NF) kidneys. Bovine insulin was added to the perfusate as a bolus and timed perfusate and urine samples were taken. Samples were assayed for insulin by RIA. Renal function parameters and insulin elimination rate constant, total clearance, and urinary clearance were calculated. Acute renal failure in Sprague Dawley rats induced by WI or UN decreased glomerular filtration rate (GFR), sodium reabsorption, and urine pH. Renal insulin clearance fell by 50 percent in the warm ischemic group, but only fell slightly in the UN group. Fractional urinary insulin clearance increased. Acute renal failure in Wistar rats from UN or WI treatment decreased GFR, urine flow, and insulin clearance. Urine pH and fractional excretion of sodium and potassium were increased. Further, insulin clearance fell by 90 percent in the NF group but was unaffected by UL. Renal tyrosine metabolism was studied at p-tyrosine perfusate concentrations of 0.0, 0.02, 0.2, and 2.0 mM. p-Tyramine concentrations were determined using a new radioenzymatic assay. Total production, urinary clearance, and fractional urinary clearance of p-tyramine and renal function parameters were calculated. Total p-tyramine production was proportional to the perfusate p-tyrosine concentration. Urinary p-tyramine clearance and fractional clearance were not different between groups. Increasing p-tyrosine levels had no effect on renal function parameters. The kidney made an important contribution to the metabolism of both insulin and p-tyrosine. Acute renal failure significantly decreased renal insulin clearance. Glucose levels should be monitored closely in diabetic patients during ARF. For the first time, the kidney was shown to be a source of urinary p-tyramine and it was demonstrated that p-tyramine production was controlled by perfusate p-tyrosine concentrations.
Degree
Ph.D.
Subject Area
Pharmaceuticals
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