ELEVATION OF [CA2-REGULATION OF MESSENGER-RNA OF PTH-PTHRP, V1A AND AT1 RECEPTORS IN KIDNEY OF DIABETIC RATS(](I) OF RENAL PROXIMAL TUBULARCELLS AND DOWN)

An elevation in intracellular calcium ([Ca2+](i)) in rats with chronic renal failure and elevated blood levels of PTH is associated with dow n-regulation of the mRNA of many proteins. Similarly, in phosphate dep leted animals that have normal renal function and low blood levels of PTH, [Ca2+](i) is elevated and the mRNA of PTH-PTHrP receptor is down- regulated. The effect of elevation in [Ca2+](i) on molecular machinery of many proteins may represent a generalized phenomenon. Diabetes mel litus may also be associated with a rise in [Ca2+](i) and therefore do wn-regulation of the mRNA of proteins may also occur. The present stud y examined the effect of streptozotocin-induced diabetes mellitus in r ats on the [Ca2+](i) of the renal proximal tubular cells and on their mRNAs of the PTH-PTHrP, V1a and AT1 receptors. The basal levels of [Ca 2+](i) of these cells increased significantly (P < 0.01) after one day of diabetes and remained elevated thereafter. There was a significant (r = 0.67, P < 0.01) direct correlation between the [Ca2+](i) of the cells and blood levels of glucose up to 350 mg/dl, and the value of [C a2+](i) plateaued with higher concentrations of glucose. Three days of amlodipine therapy prevented and reversed the elevated levels of [Ca2 +](i) despite marked hyperglycemia. The mRNA of all three receptors in the kidney were down-regulated and this defect was prevented by amlod ipine which normalized the [Ca2+](i) of the cells. The results show th at: (1) the hyperglycemia of IDDM in rats causes a significant elevati on in the basal levels of [Ca2+](i) of the renal proximal tubular cell s and down-regulation of their mRNA of PTH-PTHrP, Via and AT1 receptor s; (2) normalization of the [Ca2+](i) of these cells by treatment of t he diabetic rats with amlodipine prevented the elevation of [Ca2+](i) and the down-regulation of the mRNA of these receptors; (3) these effe cts occurred in the presence of normal renal function and normal blood of PTH and phosphorus.