title: Elevation of [Ca2+]i of renal proximal tubular cells and down-regulation of mRNA of PTH-PTHrP, V1a and AT1 receptors in kidney of diabetic rats.
abstract: An elevation in intracellular calcium ([Ca2+]i) in rats with chronic renal failure and elevated blood levels of PTH is associated with down-regulation of the mRNA of many proteins. Similarly, in phosphate depleted 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 mellitus may also be associated with a rise in [Ca2+]i and therefore down-regulation of the mRNA of proteins may also occur. The present study examined the effect of streptozotocin-induced diabetes mellitus in rats 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 [Ca2+]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 [Ca2+]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 amlodipine which normalized the [Ca2+]i of the cells. The results show that: (1) the hyperglycemia of IDDM in rats causes a significant elevation in the basal levels of [Ca2+]i of the renal proximal tubular cells and down-regulation of their mRNA of PTH-PTHrP, V1a and AT1 receptors; (2) normalization of the [Ca2+]i of these cells by treatment of the diabetic rats with amlodipine prevented the elevation of [Ca2+]i and the down-regulation of the mRNA of these receptors; (3) these effects occurred in the presence of normal renal function and normal blood of PTH and phosphorus.
authors.affiliation: Division of Nephrology, University of Southern California School of Medicine, Los Angeles, USA.
authors.forename: W
authors.initials: W
authors.lastname: Marcinkowski
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Smogorzewski
authors.forename: S G
authors.initials: SG
authors.lastname: Massry
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044168:Receptor, Parathyroid Hormone, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018016:Receptors, Parathyroid Hormone / Q000235:genetics; D017483:Receptors, Vasopressin / Q000235:genetics
chemical_list: D002121:Calcium Channel Blockers; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone; D017483:Receptors, Vasopressin; D017311:Amlodipine; D000803:Angiotensin I; D002118:Calcium