Hypercalcemia stimulates expression of intrarenal phospholipase A(2) and prostaglandin H synthase-2 in rats - Role of angiotensin II AT(1) receptors

被引:32
作者
Mangat, H
Peterson, LN
Burns, KD
机构
[1] OTTAWA GEN HOSP,DIV NEPHROL,OTTAWA,ON K1H 8L6,CANADA
[2] UNIV OTTAWA,DEPT PHYSIOL,OTTAWA,ON,CANADA
[3] UNIV OTTAWA,DEPT PEDIAT,OTTAWA,ON,CANADA
[4] UNIV OTTAWA,DEPT MED,OTTAWA,ON,CANADA
关键词
prostaglandin H synthase-1; prostaglandin E-2; losartan; kidney; Western blot;
D O I
10.1172/JCI119725
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
In chronic hypercalcemia, inhibition of thick ascending limb sodium chloride reabsorption is mediated by elevated intrarenal PGE(2). The mechanisms and source of elevated PGE(2) in hypercalcemia are not known, We determined the effect of hypercalcemia on intrarenal expression of cytosolic phospholipase A(2) (cPLA(2)), prostaglandin H synthase-1 (PGHS-1), and prostaglandin H synthase-2 (PGHS-2), enzymes important in prostaglandin production, In rats fed dihydrotachysterol to induce hypercalcemia. Western blot analysis revealed significant upregulation of both cPLA(2) and PGHS-2 in the kidney cortex and the inner and outer medulla. Immunofluorescence localized intrarenal cPLA(2) and PGHS-2 to interstitial cells of the inner and outer medulla, and to macula densa and cortical thick ascending limbs in both control and hypercalcemic rats. Hypercalcemia had no effect on intrarenal expression of PGHS-1. To determine if AT(1) angiotensin II receptor activation was involved in the stimulation of cPLA(2) and PGHS-2 in hypercalcemia, we treated rats with the AT(1) receptor antagonist, losartan. Losartan abolished the polydipsia associated with hypercalcemia, prevented the increase in cPLA(2) protein in all regions of the kidney, and diminished PGHS-2 expression in the inner medulla. In addition, losartan completely prevented the increase in urinary PGE(2) excretion in hypercalcemic rats, Intrarenal levels of angiotensin II were unchanged in hypercalcemia. These data indicate that hypercalcemia stimulates intrarenal cPLA(2) and PGHS-2 protein expression. Our results further support a role for angiotensin II, acting on AT(1) receptors, in mediating this stimulation.
引用
收藏
页码:1941 / 1950
页数:10
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