Abstract: TH-PO0027
Sex-Dependent Adaptation of Intestinal Sodium-Dependent Transporters After Tenapanor Treatment in Rats
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Liu, Yue, University College London, London, England, United Kingdom
- Dai, Zhuo, University College London, London, England, United Kingdom
- Zheng, Zhiran, University College London, London, England, United Kingdom
- Marks, Joanne, University College London, London, England, United Kingdom
Background
The sodium/hydrogen exchanger 3 (NHE3) is a key transporter responsible for sodium and fluid absorption in the intestine and proximal tubules. Tenapanor, a minimally absorbed small-molecule inhibitor of NHE3, is used clinically for treating CKD-associated hyperphosphatemia. While sex differences in renal epithelial transport are increasingly recognized, comparable differences in the intestine remain poorly understood. During tenapanor treatment studies, we observed greater diarrhea severity, intestinal fluid accumulation, and cecal enlargement in female rats, prompting further investigation of sex-dependent regulation of intestinal transporters. Given the proposed coordinated regulation of NaPi2b and SGLT1 by NHE3, the impact of tenapanor on these proteins was evaluated.
Methods
Nine-week-old male and female Sprague-Dawley rats received 0.5mg/kg tenapanor by oral gavage for 4 consecutive days, while vehicle-treated animals served as controls. Intestinal mucosa from duodenum, jejunum and ileum were collected following euthanasia, and brush border membrane vesicles were prepared. Protein expression of NHE3, NaPi2b, and SGLT1, was assessed by western blotting.
Results
Control male rats exhibited significantly higher NHE3 expression in jejunum, whereas female rats demonstrated a non-significant comparable trend. Interestingly, direct sex comparison showed higher duodenal NHE3 expression in males compared to females (4.4 fold, p<0.05), with no significant differences observed in the jejunum or ileum. Following tenapanor treatment, NHE3 expression increased in duodenum (5.1 fold, p<0.05), jejunum (2.7 fold, p<0.05), and ileum (3.5 fold, p<0.01) in female rats, whereas male rats demonstrated increased NHE3 expression only in the jejunum (2.5 fold, p<0.05) and ileum (2.9 fold, p<0.05). In contrast, NaPi2b and SGLT1 expression showed no significant differences after treatment nor between sexes.
Conclusion
These findings demonstrate sex-dependent intestinal adaptation to tenapanor-induced NHE3 inhibition. Female rats exhibited broader regional upregulation of NHE3 expression following tenapanor treatment, although this does not appear to counteract the tenapanor-induced diarrhea. These results highlight sex as an important biological variable during NHE3 inhibition, and may have implications for sex-specific gastrointestinal sensitivity and tolerability during tenapanor treatment.