Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors.

Abstract

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. (

Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

“…Cl -transport-dependent activation of the MAPKs ERK and p38 has recently been suggested in cultured cells (25). However, tyrosine phosphorylation (30) could also stimulate MD COX-2 as well as activation of phospholipase A 2 , and increased substrate availability could be the cause of acute PGE 2 generation (31). The biosensor technique should provide a novel tool that will help to clarify in detail the intracellular signaling mechanisms involved in MD NaCl transport and related PGE 2 production in response to low [NaCl] L during salt deprivation.…”

Diabetes Insipidus: A Review

“…Hypokalemia also can induce thirst leading to associated polyuria and polydipsia [90]. Hypercalcemia (plasma calcium >11 mg/ dL) causes impaired countercurrent multiplier function in the nephron associated with decreased NaCl reabsorption in the TAL, in part, due to increased PGE-2 production [91]. Hypercalcemia also may decrease AQP2 expression [92].…”

Angiotensin II attenuates renal cortical cyclooxygenase-2 expression

“…We would favor the latter possibility because studies by us (27) and others (33) have indicated that in immature and young adult rats, there are significantly more COX-2-expressing cTALH cells than in older adult rats. Furthermore, an increased number of COX-2-positive cTALH cells is seen with low-salt diet (14) or hypercalcemia (50).…”

“…Mangat et al (50) recently determined that increased COX-2 expression in the renal papilla in response to chronic hypercalcemia was significantly decreased by losartan. We did not examine COX-2 expression in the papilla in response to ACE inhibition or AT 1 R antagonism, but it is of interest that papillary COX-2 expression increases in response to a high-salt diet (15,16), suggesting that different regulatory mechanisms are operative for papillary and cTALH/macula densa COX-2 expression.…”