Endogenous prostaglandin E2 mediates inhibition of rat thick ascending limb Cl reabsorption in chronic hypercalcemia.

Abstract

The hypothesis that endogenous PGE2 mediates defective thick ascending limb (TAL) Cl reabsorption (percent delivered load: FRY0%) in rats with vitamin D-induced chronic hypercalcemia (HC) was tested by measuring FRG% in loop segments microperfused in vivo in HC and control rats treated acutely with indomethacin (Indo) or its vehicle, and obtaining the corresponding outer medullary IPGE2J. Microperfusion conditions were developed in which FR0% was exclusively furosemide sensitive. To determine the cellular mechanism, tubules were perfused acutely with forskolin (FSK), cAMP, or the protein kinase C inhibitor staurosporine (SSP). Outer medullary [PGE21 in HC rats was 9 to 10 times greater than control and could be normalized by Indo. FR0% was 20% lower in HC rats infused with vehicle, and Indo, FSK, and cAMP returned FRa% to normal despite sustained HC. Indo or FSK had no effect on FR0% in control rats and Indo did not prevent inhibition of FR0% by luminal PGE2 (1 gM). Luminal SSP (lo-7, 10-8 M) in HC did not return FR0% to control values. We conclude that impaired TAL FR0,% in HC occurs at a precAMP site and is due to endogenous PGE2 and not to HC. (J.

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

“…Our data strongly support this hypothesis. First, these studies demonstrate that increased water intake, which is consistently observed in hypercalcemic rats (5,8,40), was abolished by administration of losartan, suggesting that polydipsic behavior in hypercalcemia is mediated by binding of Ang II to the AT 1 receptor. Second, losartan prevented the increase in cPLA 2 expression in hypercalcemic animals in all kidney regions, and inhibited increased PGHS-2 expression in the inner medulla without affecting expression in the cortex and outer medulla.…”

“…Inhibition of thick ascending limb chloride reabsorption in hypercalcemia has been linked to increased prostaglandin levels in the kidney (8). There have been no studies, however, addressing either regulation of enzymes involved in prostaglandin synthesis or determination of the source of increased prostaglandins in hypercalcemia.…”

“…In DHT-induced hypercalcemia, blood calcium levels are significantly elevated by 2 d, as is water intake, two events that are independent of, and not responsible for, the concentrating defect that is evident by day 3 (6). The concentrating defect has been shown to be mediated by intrarenal PGE 2 , levels that are significantly elevated in hypercalcemia (8). A possible mechanism for this defect is suggested by the recent study of Kaji et al (30), who demonstrated that PGE 2 inhibits Na-K-2Cl cotransport in medullary thick ascending limb cells by downregulating the number of functioning cotransporters.…”

“…Renal PGE 2 excretion is strikingly elevated in hypercalcemic rats (6,7), suggesting that PGE 2 may be involved in mediating this defective NaCl reabsorption. In rats with vitamin D-induced chronic hypercalcemia, outer medullary PGE 2 levels are increased, and PGE 2 appears to mediate the inhibition of thick ascending limb NaCl transport at a step proximal to the generation of cAMP (8).…”

Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats

“…Interestingly, renal excretion of PGE 2 is significantly increased in rats with hypercalcemia (39,57), and it has been suggested that elevated PG in kidney may participate in the vasopressin-resistant urinary concentration in hypercalcemia (57). Consistent with this possibility, it was demonstrated that outer medullary PGE 2 concentration is significantly high in hypercalcemic rats, and fractional chloride reabsorption percentage (F RCl% ) in isolated loop segments microperfused in vivo was markedly low compared with control rats (51). This possibility was further supported by an observation that acute systemic treatment with indomethacin in hypercalcemic rats returned F RCl% to normal values as well as reducing PGE 2 concentration in the outer medulla (51).…”