Abstract TAC277: Gut-Selective NHE3 Inhibition Attenuates Salt-Sensitive Hypertension and Renal Damage in Dahl SS Rats

Introduction & Hypothesis: Na+/H+ exchanger isoform 3 (NHE3) is a critical mediator of sodium absorption and is primarily expressed on the apical membrane of renal proximal tubular and intestinal epithelial cells. Targeting NHE3 in the kidney is an established strategy for mitigating sodium retention and fluid overload in the setting of chronic kidney disease and hypertension, but the specific contribution of intestinal NHE3 in blood pressure regulation is largely unexplored, especially in the context of salt-sensitive hypertension. Given that excessive dietary sodium is etiologically relevant to this disease, the current study hypothesized that oral administration of tenapanor – a gut-restricted, FDA-approved NHE3 inhibitor – would attenuate hypertension and renal damage in the Dahl Salt-Sensitive (SS) rat, a widely used preclinical model of salt-sensitive hypertension. Methods: 8 week old male SS rats on a low salt diet (0.4% NaCl, AIN-76A) were implanted with telemeters (n=5-6). At 9 weeks, animals started daily oral gavage of either PBS control or tenapanor (1 week at 3mg/kg, followed by 2 weeks at 1mg/kg) while being switched to a high salt diet (4.0% NaCl) for 3 weeks. Results: There were no significant differences in mean arterial pressure (MAP) during low salt. After high salt challenge, tenapanor-treated rats exhibited significantly lower MAP compared to controls (130±1 vs 154±6 mmHg, p<0.05). Tenapanor treatment improved renal damage, indicated by mitigated albuminuria (70±12 vs 300±51 mg/day, p<0.01), renal hypertrophy (2.8±0.1 vs 3.3±0.1 g, p<0.001), and medullary protein casts (3.17±0.35 vs. 12.07±1.39%, p<0.01). There were no differences in urinary Na+, K+, or creatinine excretion. Flow cytometric analysis of immune cells revealed tenapanor significantly reduced renal immune cell infiltration of CD45+ leukocytes (25% reduction), CD3+ T cells (29%), CD4+ T helper cells (32%), CD8+ cytotoxic T cells (23%), and CD45R+ B cells (56%, all p<0.05). In the lamina propria of the small intestines, there was a specific reduction in CD8+ cytotoxic T cells (14% reduction, p<0.05). No significant differences in circulating or colonic lamina propria immune profiles were observed. Conclusions: These findings highlight a potential role for intestinal NHE3 in salt-sensitive hypertension, whereby gut-specific NHE3 inhibition attenuates salt-induced hypertension, renal damage, and inflammation in both the gut and kidney, independent of Na+ absorption in the gut.