Role of the N-methyl-D-aspartate Receptor GluN2D subunit in Blood Pressure Regulation Open Access

Abstract

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated heterotetrameric ion channels studied in the central nervous system but also expressed in the kidney, where their function remains poorly understood. Previous work showed that the GluN2C subunit contributes to renal vasodilation and blood pressure regulation. This study investigated the role of another NMDAR subunit, GluN2D, in salt and water homeostasis and blood pressure regulation. We hypothesized that GluN2D modulates fluid balance and contributes to the hypertensive response.

              Systolic blood pressure (SBP), urinary osmolality, renal clearances, and metabolic balance were assessed in wild-type (WT) and GluN2D knockout (2DKO) mice, with or without chronic angiotensin II (AII) infusion. In males, WT mice developed hypertension, whereas GluN2D ablation exhibited an attenuated response (AII WT = 160.9 ± 11.2 mmHg vs. AII 2DKO = 109.8 ± 4.0 mmHg; β = 0.65 vs. β = −0.47; p = 0.01). A sex-specific response was observed, as female mice did not develop hypertension.

           Water conservation mechanisms were not altered by GluN2D ablation. No differences were observed in urinary osmolality, free water clearance, or AQP1/AQP2 expression between WT and 2DKO mice under basal or AII-infused conditions. Under water restriction, both genotypes increased urine concentration although AII attenuated this response.

           Electrolyte balance revealed increased sodium excretion in 2DKO mice, suggesting a renal mechanism. AII increased sodium excretion in WT mice (0.32 ± 0.04 vs. 0.12 ± 0.05 mmol/day, p < 0.05), whereas no difference was observed between vehicle- and AII-treated 2DKO mice (0.25 ± 0.02 vs. 0.22 ± 0.03 mmol/day, p = 0.7). Renal hemodynamic studies showed a trend toward higher renal blood flow and lower vascular resistance in 2DKO mice.

           In conclusion, GluN2D ablation protects against AII-induced hypertension through enhanced natriuresis, likely mediated by reduced renal vascular resistance, rather than altered water conservation.

Table of Contents

Table of Contents

I.    Introduction. 1

a.     Anatomy and Functions of the Kidneys 1

a.i. The nephron, the functional unit of the Kidney. 2

a.ii Renal hemodynamics and autoregulation. 4

a.iii. Osmolality, Renal Clearance, and Free Water Clearance. 5

b.     Blood pressure regulation and the kidneys 6

b.i. Blood pressure and the RAAS pathway. 6

b.ii. Pressure-natriuresis 7

b.iii. Angiotensin II infusion. 8

b.iv. Hypertension and the Water Conservation Theory. 9

c.     Proteins of Interest 9

c.i. Structure and Function of the N-methyl D-aspartate receptor 10

c.ii NMDAR in the Kidneys 11

c.iii. Structure and Function of Aquaporin-I and Aquaporin-II 13

d.     Hypothesis 13

II. Methodology. 13

a.     Animals used in this study. 13

b.     Blood pressure measurements 14

b.i. Blood pressure measurement procedure. 14

b.ii. Data interpretation and analysis 15

c.     Drug infusion via minipump implantation. 16

d.     Electrolyte collection and analysis of urine and feces 17

d.i. Urine and feces collection: 17

d.ii. Urine Analysis 18

d.iii. Feces Analysis 20

e.     Immunoblotting. 20

e.i. Western Blot 20

e.ii. Western Blot protein quantification. 24

f.     Evaluation of Renal Blood Flow and Autoregulatory Measurements 25

g.     Statistical Analysis 26

III.      Results. 27

a.     Blood pressure comparison between genetic ablated Grin2D mice (2DKO) and WT mice: an evaluation of salt-sensitivity. 27

b.     Blood pressure response to angiotensin II infusion in male and female mice with and without genetic ablation of the Grin2D gene. 28

c.     Exploration of water conservation mechanisms 31

d.     No significant difference in expression of Aquaporin-I and Aquaporin-II channels for 2DKO mice and WT mice. 34

e.     Electrolyte excretion and urine volume in 2DKO mice. 36

f.     Renal hemodynamic studies 39

IV.      Discussion and Conclusion. 40

V.       References. 47

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.A.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell Biology, Physiology Biology, General
Keyword	Renal Physiology Kidneys Renal Medicine NMDA Receptors
Committee Chair / Thesis Advisor	Arri Eisen, Emory University
Committee Members	Richard Himes, Emory University Cesar Andres Romero, Emory University Douglas C. Eaton , Emory University

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