Sodium/hydrogen exchangers (NHEs) play a major role in Na⁺ absorption, cell volume regulation, and intracellular pH regulation. Of the nine identified mammalian NHEs, three (NHE2, NHE3, and NHE8) are localized on the apical membrane of epithelial cells in the small intestine and the kidney. Although the regulation of NHE2 and NHE3 expression has been extensively studied in the past decade, little is known about the regulation of NHE8 gene expression under physiological conditions. The current studies were performed to explore the role of epidermal growth factor (EGF) on NHE8 expression during intestinal maturation. Brush-border membrane vesicles (BBMV) were isolated from intestinal epithelia, and Western blot analysis was performed to determine NHE8 protein expression of sucking male rats treated with EGF. Real-time PCR was used to quantitate NHE8 mRNA expression in rats and Caco-2 cells. Human NHE8 promoter activity was characterized through transfection of Caco-2 cells. Gel mobility shift assays (GMSAs) were used to identify the promoter sequences and the transcriptional factors involved in EGF-mediated regulation. Our results showed that intestinal NHE8 mRNA expression was decreased in EGF-treated rats and Caco-2 cells, and NHE8 protein abundance was also decreased in EGF-treated rats. The activity of the human NHE8 gene promoter transfected in Caco-2 cells was also reduced by EGF treatment. This could be explained by reduced binding of transcription factor Sp3 on the NHE8 basal promoter region in the presence of EGF. Pretreatment with MEK1/2 inhibitor UO-126 could prevent EGF-mediated inhibition of NHE8 gene expression. In conclusion, this study showed that EGF inhibits NHE8 gene expression through reducing its basal transcription, suggesting an important role of EGF in regulating NHE expression during intestinal maturation.

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The Na⁺/H⁺ exchanger transporters (NHE) play an important role in various biologic processes including Na⁺ absorption, intracellular pH homeostasis, cell volume regulation, proliferation, and apoptosis. The wide expression pattern and cellular localization of NHEs make these proteins pivotal players in virtually all human tissues and organs. In addition, recent studies suggest that NHEs may be one of the primeval transport protein forms in the history of life. Among the different isoforms, the most well-characterized NHEs are the Na⁺/H⁺ exchanger isoform 1 (NHE1) and Na⁺/H⁺ exchanger isoform 3 (NHE3). However, Na⁺/H⁺ exchanger isoform 8 (NHE8) has been receiving attention based on its recent discoveries in the gastrointestinal tract. In this review, we will discuss what is known about the physiological function and potential role of NHE8 in the main organ systems, including useful overviews that could inspire new studies on this multifaceted protein.

Loss of Na⁺/H⁺ exchanger isoform 8 (NHE8), a Slc9 family of exchanger that contributes to sodium uptake, cell volume regulation, and intracellular pH homeostasis, resulted in dysbiosis with reduction of butyrate-producing bacteria and decrease of Muc2 production in the intestine in mice. Introducing fecal microbiota transplantation (FMT) and VSL#3 in NHE8 knockout (NHE8KO) mice failed to rebalance the microbiota in these mice. Furthermore, administration of FMT, VSL#3, and sodium butyrate was unable to restore mucin production in the absence of NHE8 in the intestine.

BACKGROUND AND AIMS: Sodium-hydrogen exchanger 8 (NHE8) is expressed in array of tissues and has pleiotropic functions beyond simply exchanging sodium and hydrogen across cell membrane. This study investigates the expression pattern of liver NHE8 and its roles in carbon tetrachloride (CCl4)-induced liver injury. METHODS: NHE8 expression pattern was investigated in mouse livers of different ages and in HepG2 cells. CCl4 was given to mice to determine NHE8 expression in CCl4induced liver injury. Tumor necrosis factor (TNF)-a and interleukin (IL)-1b were used to treat HepG2 cells to evaluate their effect on NHE8 expression. The CCl4-induced acute and chronic liver injuries were also used in NHE8KO mice to determine the role of NHE8 deficiency in liver injury. RESULTS: NHE8 was mainly detected in the peripheral area of hepatocytes in mouse liver and in HepG2 cells. The liver NHE8 expression was 47% of NHE1, and liver NHE8 expression was the lowest at suckling age and reached plateau at 4 weeks of age. Similar to dextran sulfate sodium colitis reduced intestinal NHE8, CCl4-induced acute liver injury also inhibited NHE8 expression. The absence of NHE8 in the liver displayed abnormal hepatocyte morphology and has elevated expression of IL-1b and Lgr5. However, unlike NHE8 deficiency enhanced dextran sulfate sodium-induced colon tissue damage, the absence of NHE8 in the liver did not exacerbate CCl4induced liver injury. Although both TNF-a and IL-1b were elevated in CCl4-induced liver injury, they could not inhibit NHE8 expression in hepatocytes, which is in contrast with TNFa-mediated NHE8 inhibition in the intestine. CONCLUSION: Liver NHE8 has unique roles that are different from the intestine.