Epithelial N-methyl-D-aspartate (NMDA) receptors mediate renal vasodilation by affecting kidney autoregulation

• Type of Material: Article
• Authors: Cesar A. Romero, Emory University; Jasmine Lim, Emory Unviersity; Hong Wang, Henry Ford Health Systems; Brandi M. Wynne, University of Utah; Peipei Ma, Emory University; Yao Jing, Emory University; Dennis C. Liotta, Emory University; Michael D'Erasmo, Emory University; Stephen F. Traynelis, Emory University; Douglas C. Eaton, Emory University; Susan M. Wall, Emory University
• Language: English
• Date: 2023-12-06
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2023.12.04.569973
• Title of Journal or Parent Work: bioRxiv
• Start Page: 569973
• Grant/Funding Agency: National Institute of Health
• Grant/Funding Information: This work was supported by the National Institute of Health NHLBI Grant K01HL155235 to C.R., and a developmental grant from the NIH-Funded Emory Specialized Center of Research Excellence in Sex Differences U54AG062334 to C.R. Supported by R01 DK-110409 to D.C.E, K01 DK-115660 and ASN Gottschalk AWARD to B.M.W, and R01 DK- 119793 to S.M.W.
• Keywords: Connecting tubule-glomerular feedback; Kidney Autoregulation; NMDA receptors; Acute Kidney Injury; ENaC
• Subject - Topics: Physiology; Kidney

Abstract

Background: N-methyl-D-aspartate receptor (NMDAR) are amino acid receptors that are well studied in brain physiology; however, their role in kidney is poorly understood. Nonetheless, NMDAR inhibitors can increase serum K+ and reduce GFR, which suggests they have an important physiological role in the kidney. We hypothesized that NMDARs in the distal nephron induce afferent-arteriole vasodilation through the vasodilator mechanism connecting-tubule-glomerular feedback (CNTGF) that involves ENaC activation. Methods and results: Using a tubule-specific transcriptome database combined with molecular biology and microscopy techniques, we showed kidney expression of NMDAR subunits along the nephron and specifically in ENaC-positive cells. This receptor is expressed in both male and female mice, with higher abundance in females (p=0.02). Microperfusing NMDAR agonists into the connecting tubule induced afferent-arteriole vasodilation (EC50 10.7 vs. 24.5 mM; p<0.001) that was blunted or eliminated with the use of NMDAR blocker MK-801 or with the ENaC inhibitor Benzamil, indicating a dependence on CNTGF of the NMDAR-induced vasodilation. In vivo, we confirmed this CNTGF-associated vasodilation using kidney micropuncture (Stop-flow pressure 37.9±2.6 vs. 28.6±1.9 mmHg, NMDAR agonist vs vehicle; p<0.01). We explored NMDAR and ENaC channel interaction by using mpkCCD cells and split-open connecting tubules. We observed increased amiloride-sensitive current following NMDAR activation that was prevented by MK-801 (1.14 vs. 0.4 μAmp; p=0.03). In split-open tubules, NMDAR activation increased ENaC activity (Npo Vehicle vs. NMDA; p=0.04). Conclusion: NMDARs are expressed along the nephron, including ENaC-positive cells, with higher expression in females. Epithelial NMDAR mediates renal vasodilation through the connecting-tubule-glomerular feedback, by increasing ENaC activity.