Low Tonicity Mediates a Downregulation of Cyclooxygenase-1 Expression by Furosemide in the Rat Renal Papilla

Kotnik, Primož, Jakob Nielsen, Tae-Hwan Kwon, Ciril Kržiš-nik, Jørgen Frøkiaer, and Søren Nielsen. Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus. Am J Physiol Renal Physiol 288: F1053-F1068, 2005. First published January 11, 2005 doi:10.1152/ajprenal.00114.2004Prostaglandins have an important role in renal salt and water reabsorption. PGE 2 is the main kidney prostaglandin and is thought to be mainly produced in the kidney inner medulla (IM). There are indications that PGE2 synthesis in nephrogenic (NDI) and central (CDI) diabetes insipidus is altered. We hypothesize that the expression of the major PGE 2 synthesis enzymes cyclooxygenases 1 and 2 (COX-1, COX-2) and membrane-associated PGE2 synthase (mPGES) is altered in the kidneys of rats with NDI and CDI. Wistar rats treated with lithium for 4 wk were used as the NDI model. One-half of the NDI model rats were additionally dehydrated for 48 h. Brattleboro (BB) rats that lack endogenous antidiuretic hormone were used as the CDI model. Expression and localization of COX-1, COX-2, and mPGES in IM, inner stripe of outer medulla (ISOM), and cortex were determined by immunoblotting and immunohistochemistry. In lithium-induced NDI, expression of COX-1, COX-2, and mPGES was markedly decreased in IM. In ISOM and cortex, COX-1 expression was marginally reduced and mPGES expression was unaltered. COX-2 expression was undetected in ISOM and marginally increased in cortex. Consistent with this, the density of COX-2-expressing cells in macula densa was significantly increased, indicating differential regulation of COX-2 in IM and cortex. Dehydration of NDI rats resulted in a marked increase in COX-2 immunolabeling in IM interstitial cells, and there was no significant change in COX-1 and mPGES expression in any kidney zone. Treatment of DDAVP in BB rats for 6 days resulted in a markedly increased expression of COX-1, COX-2, and mPGES in IM. In the cortex, there were no changes in the expression of COX-1 and mPGES, whereas COX-2 expression was decreased. These results identify markedly reduced expression of COX-1, COX-2, and mPGES in IM in lithium-induced NDI. Furthermore, there were major changes in the expression of COX-1, COX-2, and mPGES in rats with CDI.cyclooxygenase-2; DDAVP; inner medullary interstitial cell; medullary osmolality; membrane-associated prostaglandin E 2 synthase; prostaglandin; urine concentration PROSTAGLANDINS, WHICH FUNCTION as autocrine and paracrine lipid mediators, play important roles in a variety of regulatory homeostatic mechanisms (36). In the kidney, prostaglandins have an important role in affecting renal hemodynamics, renin release, tubular sodium, and water reabsorption (12). The main prostaglandin in the kidney is prostaglandin E 2 (PGE 2 ), which is synthesized from arachidonic acid in a two-step enzymatic reaction. Arachidonic acid is first converted to an unstable intermediate PGH 2 by one of the two cyclooxygenase isoforms, COX-1 or COX-2. This rate-limiting step is then followe...

“…and body fluid volume on COX expression (3,44). Thus these findings support that COX-2-derived PGs participate in the regulation of urinary water excretion.…”

Section: Effect Of Dehydration On the Expression Of Cox-2 In Lithium-supporting

confidence: 70%

Section: Changes In Cox-1 Cox-2 and Mpges Expression In Lithium-indmentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus

Kotnik¹,

Nielsen²,

Kwon³

et al. 2005

“…Changes in PGES expression were parallel to COX-1, and these parameters were further coordinated with an ϳ65% decrease in PGE 2 urinary output. Currently available data provide no specific mechanisms for these changes, and most data on COX-1 have come from studies in the renal inner medulla where tonicity appears to play a role in its regulation (6,23). Yet, the present conditions cannot easily be related with cortical cell volume or transport status.…”

Section: Discussionmentioning

confidence: 99%

Renal cortical regulation of COX-1 and functionally related products in early renovascular hypertension (rat)

Theilig¹,

Dębiec²,

Nafz³

et al. 2006

volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E 2 (PGE2) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B 2 receptor blockade using candesartan (cand) or the B 2 antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham ϩ cand, 2K1C ϩ cand, sham ϩ Hoe, 2K1C ϩ Hoe) were treated to map expression of parameters controlling PGE 2 synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE 2 levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B 2 receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.cyclooxygenase; nitric oxide synthase; bradykinin RENOVASCULAR HYPERTENSION (RVH) is a form of secondary hypertension. The two kidney-one clip rodent model of RVH (2K1C; Goldblatt model) is similar to unilateral RVH in humans. The defect is highly dependent on the enhanced activity of the renin-angiotensin system (RAS). Decreased renal perfusion pressure in the compromised kidney maximally activates the RAS, and its inability to balance the rise in blood pressure is partly the result of elevated ANG II levels. The nonstenotic kidney is subject to elevated perfusion pressure, responding with "pressure natriuresis" to lower blood pressure by the excretion of sodium. In the light of systemically elevated ANG II levels and the distinct constellation of the renal perfusion pressures, the RVH model is considered by some to be wholly one of increased peripheral vascular resistance, whereas others emphasize the role of volume retention (13; for a review, see Ref. 14). For the latter, elevated ANG II levels prevail in both kidneys in short-term and maintenance phase affecting both tubular transport and renal hemodynamics thereby causing long-term impairments in sodium balance regulation (29,30).Biological mechanisms with protective effects against hypertension and organ damage have received continuous interest and have therefore been studied also in RVH. In particular, paracrine and endocrine systems with protective potency have been analyzed for...

“…PGE 2 synthesis in the collecting duct cells is modulated by osmolality (20). Along this line, it is consistently demonstrated that renal medullary COX-2 expression is induced by WD (13, 45); the opposite is true in that the COX-2 expression is reduced by water loading or chronic furosemide infusion that eliminates renal medullary osmotic gradient (4). Extensive in vitro studies have defined the signaling transduction pathway leading to osmotic regulation of COX-2 in collecting duct and renal medullary interstitial cells that primarily involve the activation of MAPK and NF-B (13,46).…”

Section: Discussionmentioning

confidence: 99%

mPGES-1-derived PGE₂ mediates dehydration natriuresis

Liu

Sun

Kakizoe

et al. 2013

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...