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

  • Organ Physiology
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Abstract

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 EP2 or EP4 receptors and/or a downregulation of renal EP1 and EP3 receptors enhances PGE2-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 EP4 receptor, whereas the expressions of the EP1 and EP3 receptors were decreased. In isolated-perfused kidneys from control mice, PGE2 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 PGE2 concentrations was absent. Similarly, prostacyclin (PGI2)-induced vasodilatation was more pronounced in endotoxemic kidneys. The enhanced vasodilatory effect was paralleled by an increase in renal vascular EP4 and prostacyclin IP receptor mRNA expression. Further, stimulation of renin secretion rate by PGE2 and PGI2 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 PGE2 in response to LPS and that the vasodilatory effect of PGE2 and PGI2 is enhanced during endotoxemia.

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Acknowledgements

The technical assistance provided by Ramona Mogge is gratefully acknowledged.

Funding

This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, SFB699/B5).

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Fahrstr. 17, 91054, Erlangen, Germany

    Manuel Meurer & Klaus Höcherl

  2. Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Poliklinik, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany

    Katharina Ebert

  3. Institute of Physiology, University of Regensburg, Regensburg, Germany

    Frank Schweda

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  1. Manuel Meurer
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Correspondence to Klaus Höcherl.

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All animal experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the local animal protection committee.

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Meurer, M., Ebert, K., Schweda, F. et al. The renal vasodilatory effect of prostaglandins is ameliorated in isolated-perfused kidneys of endotoxemic mice. Pflugers Arch - Eur J Physiol 470, 1691–1703 (2018). https://doi.org/10.1007/s00424-018-2183-3

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