mPGES-1-derived PGE₂ mediates dehydration natriuresis

Abstract

is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na ϩ excretion accompanied with normal plasma Na ϩ concentration and osmolality. In contrast, WD-induced elevation of urinary Na ϩ excretion was completely abolished in mPGES-1 knockout (KO) mice in parallel with increased plasma Na ϩ concentration and a trend increase in plasma osmolality. WD induced a 1.8-fold increase in urinary PGE2 output and a 1.6-fold increase in PGE2 content in the renal medulla of WT mice, both of which were completely abolished by mPGES-1 deletion. Similar patterns of changes were observed for urinary nitrate/nitrite and cGMP. The natriuresis in dehydrated WT mice was associated with a significant downregulation of renal medullary epithelial Na channel-␣ mRNA and protein, contrasting to unaltered expressions in dehydrated KO mice. By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE2 contributes to dehydration natriuresis likely via NO/ cGMP. mPGES-1; PGE2; dehydration natriuresis; cGMP; nitric oxide DEHYDRATION LEADS TO THE DEPLETION of plasma volume and the increase of body fluid osmolality. Such changes trigger the homeostatic response to conserve the fluids through the thirst mechanism, vasopressin release, and potentiated renal reabsorption. During the early stage of dehydration, an important physiological response is an acute increase in urinary Na ϩ excretion, a phenomenon termed dehydration natriuresis. This response will help prevent the further rise of plasma Na ϩ concentration and extracellular tonicity. Dehydration natriuresis has been demonstrated in humans as well as in other mammalian species, including dog, sheep, rat, and mouse (1,7,18,28,31,33,36,37). A number of factors such as neurohypophysial hormones and serum-and glucocorticoid-inducible kinase (Sgk1) are implicated in mediating dehydration natriuresis but the precise mechanism remains unclear.PGE 2 is a major prostanoid in the kidney and possesses natriuretic property owing to its ability to inhibit Na ϩ transport in the distal nephron (3, 6, 39, 43). The elevation of urinary PGE 2 in response to dehydration accompanied with increased renal medullary cyclooxygenase (COX)-2 expression has also been well-demonstrated (29,41,47). However, the functional implication of dehydration-induced renal PGE 2 synthesis is still incompletely understood.To date, three PGE synthases (PGES) have been cloned, including microsomal PGE...

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