Journal
CLINICAL SCIENCE
Volume 134, Issue 8, Pages 941-953Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20200065
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK110621]
- American Heart Association Transformational Research Award [19TPA34850116]
- LeDucq Foundation
- Danish Medical Research Council
- Novo Nordisk Foundation
- American Heart Association [18PRE33990236, 19POST34400026]
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The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3(IEC-KO)). Before tamoxifen administration, the phenotype and blood parameters of NHE3(IEC-KO) were unremarkable compared with control mice. After tamoxifen administration, NHE3(IEC-KO) mice have undetectable levels of NHE3 in the intestine. NHE3(IEC-KO) mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3 lEc-K degrees mice show a similar to 25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3(IEC-KO) mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.
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