A Novel Mechanism of Pressure Natriuresis as Revealed in Global, Kidney‐selective and Conditional Proximal Tubule‐specific NHE3 Knockout Mice
Authors: Li Xiao C , Soleimani Manoocher , Zhuo Jia L 
Published: November 2023

It is well recognized that a physiological pressure natriuretic response plays a key role in maintaining normal blood pressure and body salt and fluid balance, and that regardless of the cause, the development and maintenance of hypertension require continuously resetting of the pressure natriuresis relationship to higher pressures. However, the mechanisms underlying pressure natriuresis responses in physiology and resetting of the pressure natriuresis relationship to higher pressures in hypertension remain incompletely understood. In the present study, we used global Na+/H+ exchanger 3‐deficient mice (Nhe3−/−), Nhe3−/− mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3−/−) as an alternative kidney‐selective Nhe3‐KO model, and conditional proximal tubule‐specific Nhe3−/− mice (PT‐Nhe3‐KO) to test the hypothesis that NHE3 in the proximal tubule of the kidney, rather than NHE3 in small intestines, is required for physiological pressure natriuretic responses in mice. One group of control and one experimental group of adult male wild‐type (WT), global Nhe3−/−, tgNhe3−/−, and PT‐Nhe3‐KO mice were anesthetized and prepared for standard pressure natriuretic experiments. Pressure natriuresis responses were studied using the mesenteric and celiac occlusion technique to elevate renal perfusion pressure equally by ~25 mmHg in all strains of mice (p<0.01). Under basal conditions, Nhe3−/−, tgNhe3−/−, and PT‐Nhe3‐KO mice had significantly lower systolic blood pressure (p<0.01) and mean intra‐arterial blood pressure than WT mice (p<0.01). 24 h fecal Na+ excretion was significantly increased (p<0.01), whereas 24 h urinary Na+ excretion was significantly reduced in both Nhe3−/− and tgNhe3−/− mice (p<0.01). By contrast, no difference was found in fecal Na+ excretion between WT and PT‐Nhe3‐KO mice, although 24 h urinary Na+ excretion was significantly increased in PT‐Nhe3‐KO mice (p<0.01). In response to increased renal perfusion pressure by ~25 mmHg, urinary Na+ excretion was increased by 4‐fold in WT mice (p<0.01), whereas it was increased by only 2‐fold in Nhe3−/− and tgNhe3−/− mice (p<0.01). By comparison, urinary Na+ excretion was increased by 7‐fold in PT‐Nhe3‐KO mice when renal perfusion pressure was increased equally by ~25 mmHg (p<0.01). In Nhe3−/− and tgNhe3−/− mice, attenuated pressure natriuretic responses were associated with abnormal intestinal structures and significant salt wasting (p<0.01). However, no abnormal structural phenotypes were observed in the intestines and kidneys of PT‐Nhe3‐KO mice. We concluded that NHE3 in the proximal tubule of the kidney, rather than NHE3 in small intestines or in distal tubular segments of the kidney, plays an important role in the regulation of physiological pressure natriuretic responses in mice.Support or Funding InformationThis work was supported by grants from National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of General Medical Sciences (2R01DK067299‐06A2 and 1R01DK102429‐01).