The renal vasodilatory effect of prostaglandins is ameliorated in isolated-perfused kidneys of endotoxemic mice.

Endotoxemia-related acute kidney injury (AKI) is associated with increased formation of prostaglandins, which may serve as a compensatory mechanism to maintain renal function. We hypothesized that an increase of renal EP or EP receptors and/or a downregulation of renal EP and EP receptors enhances PGE-induced renal vasodilatation. Injection of lipopolysaccharide (LPS; 3 mg/kg i.p.) increased microsomal prostaglandin E synthase (mPGES)-1 and prostacyclin synthase expression, whereas mPGES-2 expression was unaltered. Further, LPS increased the mRNA abundance for the prostaglandin EP receptor, whereas the expressions of the EP and EP receptors were decreased. In isolated-perfused kidneys from control mice, PGE exerted a dual effect on renal vascular tone, inducing vasodilatation at lower concentrations and vasoconstriction at higher concentrations. In kidneys from endotoxemic mice, the vasodilatory component was more pronounced, whereas the vasoconstriction at higher PGE concentrations was absent. Similarly, prostacyclin (PGI)-induced vasodilatation was more pronounced in endotoxemic kidneys. The enhanced vasodilatory effect was paralleled by an increase in renal vascular EP and prostacyclin IP receptor mRNA expression. Further, stimulation of renin secretion rate by PGE and PGI was enhanced in endotoxemic kidneys. Pretreatment with the cyclooxygenase (COX)-2 inhibitor SC-236 (10 mg/kg) did not alter the basal GFR, but augmented the LPS-induced decline in GFR, and attenuated the LPS-induced increase in plasma renin concentration in vivo. Our data suggest that an activation of the COX-2/mPGES-1 synthetic pathway is responsible for the increased renal formation of PGE in response to LPS and that the vasodilatory effect of PGE and PGI is enhanced during endotoxemia.