Renal Hemodynamic and Blood Pressure Effects of the Glutamate Receptor GluN2C in Liddle Syndrome

The glutamate receptor subunit GluN2C is a cationic channel of the NMDA receptor family expressed in the distal nephron. GluN2C exhibits sexual dimorphism, with females showing 2–5-fold higher expression than males. We previously demonstrated that GluN2C increases ENaC activity. In addition, GluN2C inhibition reduces ENaC-dependent afferent arteriole vasodilation mediated by connecting tubule–glomerular feedback (CNTGF). Impaired vasodilation secondary to GluN2C inhibition may increase blood pressure (BP). Conversely, GluN2C inhibition reduces ENaC activity, potentially decreasing sodium reabsorption and lowering BP. Thus, the net BP effect of GluN2C inhibition in an ENaC-dependent salt-sensitive model remains unclear. We hypothesized that GluN2C inhibition would induce a subacute BP increase due to vasodilation impairment, followed by long-term normalization secondary to reduced ENaC activity in Liddle syndrome mice. Methods Male and female Liddle syndrome mice and wild-type (WT) controls (Sv129, Taconic) were studied under normal- and high-salt diets. BP was measured over 16 days by tail-cuff plethysmography. Osmotic minipumps delivered a non-selective NMDA receptor blocker (MK-801), a selective GluN2C inhibitor (DQP-997-74), or vehicle. In a subset receiving acute MK-801 injection, renal blood flow spectral analysis and autoregulatory responses were assessed by laser Doppler flowmetry. RNA and GltuN2C protein expression were quantified using RNAscope and immunofluorescence. Results Under a normal-salt diet, MK-801 or DQP-997-74 increased BP in both sexes during the first 7 days (SBP 130.2 ± 14 vs. 104.3 ± 17 mmHg, p 0.05). Under a high-salt diet, male Liddle mice developed salt-sensitive hypertension (ΔSBP 26.7 ± 14 mmHg, p = 0.04), whereas females did not. MK-801 normalized BP in hypertensive males by day 5. In normotensive females, MK-801 induced a similar pattern to that observed under normal salt (subacute BP increase followed by normalization). Grin2c RNA expression did not differ between WT and Liddle mice or between sexes. As expected, protein abundance was higher in WT females than in males. In contrast, Liddle mice showed the opposite pattern: male Liddle mice exhibited a threefold increase in GluN2C protein compared with Liddle females and WT males (1506 ± 360 vs. 437.3 ± 172.3 positive cells/µm 2 , p < 0.01). Conclusion GluN2C inhibition impairs CNTGF-mediated vasodilation, leading to a subacute BP increase in Liddle syndrome mice. Over time, BP normalizes, likely due to reduced ENaC activity and activation of pressure-natriuresis. A marked sex difference was observed, with male salt sensitivity potentially related to increased GluN2C protein expression in Liddle mice. Grin2c emerges as a potential modulator of ENaC in Liddle syndrome. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.