PS-B09-8: N-METHYL-D-ASPARTATE (NMDA) RECEPTORS INDUCE RENAL VASODILATION AND REGULATES BLOOD PRESSURE

Document Type

Conference Proceeding

Publication Date

1-1-2023

Publication Title

J Hypertens

Abstract

Introduction: N-methyl-D-aspartate receptors (NMDAr) are glutamate/glycine receptors expressed in the kidney. NMDAr induce renal vasodilation through an unknown mechanism. Connecting tubule-glomerular feedback (CNTGF) is a vasodilator feedback mechanism, initiated by ENaC in the connecting tubule producing afferent arteriole (AffA) vasodilatation and promoting sodium excretion. We hypothesized that NMDAr activation stimulate CNTGF and that the inhibition of NMDAr decrease CNTGF vasodilation inducing hypertension.

Methods: We explore the presence of NMDAr receptors in mouse by transcriptome analysis of microdisseted tubules segments, total kidney western blot and immunofluorescence. We used mpkCCD cells (mouse principal cells) to explore the interaction between NMDAr and ENaC in PC using trasnwell current analysis and split-open tubule using patch clamp method. To determine the effect of NMDAr on CNTGF, we measured CNTGF-mediated AffA dilation in the presence or absence of NMDAr agonists glutamate and glycine with and without NMDAr antagonist (MK801), using a double-microperfusion method in rabbits, and invivo by micropunture technique in rats. To evaluate the effect of NMDAr on blood pressure (BP), we measure BP in NMDA 2C global knock out mice. BP was measure using tail cuff methods. To confirm the effect of NMDAr on BP we infused subcutaneously NMDAr inhibitor MK801 for 7 days in a gain of function β ENaC mutated allele mice on129/Sv background on normal salt diet.

Results: NMDAr was found to be expressed in connecting tubule and co-localized with AQP2 and ENaC. In mpkCCD cells and open split tubules, NMDAr activation increase ENaC activity, while NMDAr inhibition decrease ENaC activity (p < 00.1). In-vitro, tubular microperfusion of NMDAr agonist increased AffA dilation (p < 0.001). NMDAr agonist-induced dilation was blunted with MK-801 (NMDAr blocker) and totally blocked with benzamil (CNTGF inhibitor). In vivo, NMDAr agonist increase CNTGF mediated vasodilation (P < 0.01). NMDAr 2C knock out mice showed high BP in comparison with wildtype (SBP 114.6 ± 7.3 vs 100.4 ± 2.2 mmHg, respectively, p = 0.01). In β ENaC mutated mice, the infusion of NMDAr inhibitor (Mk-801) induces hypertension (SBP 146 ± 8 mmHg) while the vehicle infused mice remained normotensives (110.7 ± 7.7 mmHg; p < 0.01).

Conclusions: NMDAr in the connecting tubule increase renal vasodilation by activating CNTGF. The genetic ablation of NMDAr 2C or the pharmacological inhibition of NMDAr increase blood pressure. Future studies need to confirm the role of NMDAr in the pathogenesis of hypertension.

Volume

41

Issue

Supplement 1

First Page

e379

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