Prostaglandin E2-9-ketoreductase as a mediator of salt intake-related prostaglandin-renin interaction

The renin-angiotensin system constitutes a major hormonal cascade regulating fluid and electrolyte balance and blood pressure (BP), the principal effector of which is angiotensin II (Ang II) (1). The vast majority of the physiological effects of Ang II are mediated by the subtype-1 (AT 1 ) angiotensin receptor; the function of the subtype-2 (AT 2 ) receptor remains to be determined (2). AT 2 receptors are present in the kidney and are upregulated by sodium depletion and Ang II (3, 4).Ang II stimulates production of prostacyclin (PGI 2 ) and prostaglandin E 2 (PGE 2 ) (5). The angiotensin receptor subtype mediating renal prostanoid formation is largely unknown. We have shown previously in the rat kidney that the AT 1 receptor mediates Ang II-induced PGE 2 production and that pharmacological blockade of the AT 2 receptor potentiates Ang II-induced PGE 2 levels (6). We also demonstrated that Ang II stimulates an increase in renal PGF 2α through an action at the AT 2 receptor (7).This study was conducted to evaluate the role of the AT 2 receptor in prostaglandin metabolism and to investigate the mechanisms involving prostaglandins in maintaining normal BP. To address these issues, we used a novel microdialysis technique and mice with targeted disruption of the AT 2 receptor gene to monitor changes in 6-keto-PGF 1α (a stable hydrolysis product of PGI 2 ), PGE 2 , PGF 2α , and cAMP (the major second messenger of PGE 2 and PGI 2 ) in renal interstitial fluid (RIF) (5, 8). MethodsTargeted disruption of the mouse AT 2 receptor gene. This procedure was performed as described (9). In brief, the coding region of embryonic stem cells (E14-1) in the third exon of the AT 2 receptor gene on the X chromosome was disrupted with a construct containing a neomycin-resistant expression cassette and herpes simplex virus thymidine-kinase expression cassette. The gene-disrupted cells were selected by G418 and ganciclovir, followed by Southern blot analysis to validate the desired gene disruption. Four targeted clones were obtained from 800 double-resistant colonies, 2 of which were injected into blastocysts derived from C57BL/6 mice, and the blastocysts were implanted into the uterus of pseudopregnant JCR mice. Of 34 chimeras, germ-line transmission occurred in 11 mice. Heterozygous female mice and wildtype (WT) male mice were mated to generate hemizygous male mice. Homozygous female mice were generated by mating heterozygous females with hemizygous males. The presence of a homozygous mutated AT 2 receptor The angiotensin subtype-1 (AT 1 ) receptor mediates renal prostaglandin E 2 (PGE 2 ) production, and pharmacological blockade of the angiotensin subtype-2 (AT 2 ) receptor potentiates the action of angiotensin II (Ang II) to increase PGE 2 levels. We investigated the role of the AT 2 receptor in prostaglandin metabolism in mice with targeted deletion of the AT 2 receptor gene. Mice lacking the AT 2 receptor (AT 2 -null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT 2 -null m...

supporting

confidence: 83%

Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor

Siragy

Senbonmatsu²,

Ichiki³

et al. 1999

“…Whereas Lifschitz et al found no difference in urinary excretion of PGE2 in rabbits oIn high or low sodium diets (38), Weber et al (39) and Stahl et al (40) reported that urinary PGE2 excretion rates were higher in rabbits during sodium depletion. The latter workers also found that in vitro PGE2 synthesis by papillary and medullary kidney slices was enhaneed in tissuie taken from sodium-depleted rabbits (40).…”

Section: Discussionmentioning

confidence: 99%

Increased renal secretion of norepinephrine and prostaglandin E2 during sodium depletion in the dog.

Oliver¹,

Pinto²,

Sciacca³

et al. 1980

A B S T R A C T To determine whether vasoactive renal hormones modulate renal blood flow during alterations of sodium balance, simultaneous measurements of arterial and renal venous concentrations of norepinephrine and prostaglandin E2 (PGE2) and of plasma renin activity, as well as renal blood flow and systemic hemodynamics were carried out in 24 sodiumdepleted and 28 sodium-replete anesthetized dogs. The mean arterial blood pressure of the sodium depleted dogs was not significantly different from that of the animals fed a normal sodium diet, but cardiac outptut was significantly lower (3.07±0.18 vs. 3.77±0.17 liters/mim, mean±SEM; P < 0.01). Despite the higher total peripheral vascular resistance in the sodiumdepleted dogs (46.1±2.9 vs. 37.0±2.1 arbitrary resistance U; P < 0.02), the renal blood flow and renal vascular resistance were not significantly different in the two groups. The arterial plasma renin activity and concentration of norepinephrine were higher in the sodium-depleted animals than in the controls; the arterial concentration of PGE2 was e(ual in both groups. The renal venous plasma renin activity was higher in the sodium-depleted dogs. Similarly, the renal venous norepinephrine concentration was higher in the sodium-depleted dogs than in the controls (457±44 vs. 196±25 pg/ml; P <0.01); renal venous PGE2 concentration was also higher in the sodium depleted dogs (92±22 vs. 48±11 pg/ml; P < 0.01). Administration of indomethacin to five sodium-replete dogs had no effect on renal blood flow. In five sodium-depleted dogs indomethacin lowered renal blood flow from 243±19 to 189+30 ml/min (P < 0.05) and PGE2 in renal venous blood from 71±14 to 15±2 pg/ml (P < 0.02). The results indicate that moderate chronic sodium depletion, in addition to enhancing the activity of the renin-angiotensin system, also increases the activity of the renal adrenergic nervous system and increases renal PGE2 synthesis. In sodiumReceived for publication 19 February 1980 and in revised form 4 June 1980. 748 depleted dogs, inhibition of prostaglandin synthesis was associated with a significant decrease in renal blood flow. The results suggest that the renal blood flow is maintained during moderate sodiulm depletion by an effect of the prostaglandins to oppose the vasoconstrictor effects of angiotensin II and the rencal sympathetic nervous system.

“…Other possible mechanisms that could account for the observed increase in RIF PGE 2 during AT 2 receptor blockade include: (1) Decreased activity of PGE 9-ketoreductase, the enzyme responsible for converting PGE 2 to PGF 2␣ . This enzyme may be stimulated by bradykinin and/or AII (19,20) during sodium depletion (7,9). We hypothesize that PGE 9-ketoreductase could be inhibited during AT 2 receptor blockade resulting in the observed marked increase in PGE 2 levels.…”

Section: Discussionmentioning

confidence: 99%

The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3', 5'-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats.

Siragy¹,

Carey²

1996

298

235

The renal effects of angiotensin II(AII) are attributed to AT 1 receptors. In contrast, the function of renal AT 2 receptors is unknown. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) prostaglandin E 2 (PGE 2 ) and cyclic guanosine 3 Ј , 5 Ј -monophosphate (cGMP) in response to dietary sodium (Na) depletion alone, or Na depletion or normal Na diet combined with the AT 1 receptor blocker, Losartan, the AT 2 receptor blocker, PD 123319 (PD), or angiotensin II, individually or combined in conscious rats. Na depletion significantly increased PGE 2 and cGMP. During Na depletion, Losartan decreased PGE 2 and did not change cGMP. In contrast, PD significantly increased PGE 2 and decreased cGMP. Combined administration of Losartan and PD decreased PGE 2 and cGMP.During normal Na diet, RIF PGE 2 and cGMP increased in response to angiotensin II. Neither Losartan nor PD, individually or combined, changed RIF PGE 2 or cGMP. Combined administration of angiotensin II and Losartan or PD produced a significant decrease in response of PGE 2 and cGMP to angiotensin II, respectively.