Transcriptional regulation of the intestinal luminal Na⁺and Cl⁻transporters

Abstract

The epithelial apical membrane Na+/H+ exchangers (NHE2, NHE3) and Cl−/HCO3− exchangers (DRA and PAT-1) are key luminal membrane transporters involved in electroneutral NaCl absorption in the mammalian intestine. During the past decade, there has been a surge of studies focusing on short-term regulation of these electrolyte transporters particularly for NHE3 regulation. However, the long-term regulation of the electrolyte transporters involving transcriptional mechanisms and transcription factors that govern their basal regulation or dysregulation in diseased states has only now started to unfold with the cloning and characterization of their gene promoters. This review updates the readers with a detailed analysis of the core promoters of NHE2, NHE3, DRA and PAT-1 and outlines the transcription factors involved in their basal regulation as well as in response to both physiological (butyrate, protein kinases, probiotics) and pathophysioloical (cytokines and high levels of serotonin) stimuli. The available information on the transcriptional regulation of the recently identified NHE8 isoform is also highlighted. This review, therefore, bridges a gap in our knowledge of the transcriptional mechanisms underlying the alterations in the gene expression of intestinal epithelial luminal membrane Na+ and Cl− transporters involved in electroneutral NaCl absorption. An understanding of the mechanisms of modulation of gene expression of these transporters is important for a better assessment of the pathophysiology of diarrhea associated with inflammatory and infectious diseases and may aid in designing better management protocols.

Effect of NSAIDs on Na+/H+ exchanger activity in rat colonic crypts

“…Both drugs were found to increase the activity of one or more hydrogen ion transport proteins, leading to a significantly higher average rate of pH recovery following alkalization with NH 4 Cl (aspirin 0.03791 Ϯ 0.002430 ⌬pH i /min; control 0.02072 Ϯ 0.001586 ⌬pH i /min and indomethacin 0.08175 Ϯ 0.007391 ⌬pH i /min; control 0.05833 Ϯ 0.005221 ⌬pH i /min). We hypothesized that this increase in acidification is a result of enhanced proton secretion through the NHE pathway, particularly the apical NHE exchangers NHE-2 and NHE-3, which are key membrane transport proteins in the mammalian GI tract (36). Perfusion with the NHE-targeted inhibitors EIPA and amiloride, as well as zoniporide dihydrochloride, led to a more specific understanding of the NHE isoforms involved.…”

The Impact of Probiotics on the Gastrointestinal Physiology

“…It has been determined that two carrier proteins play a role in the sodium absorption; "sodium hydrogen exchanger-2" (NHE-2) and NHE-3 which are the members of "solute carrier family-9" (SLC9) (Malakooti et al, 2011). While NHE-2 is expressed mostly in colon, NHE-3 is expressed mainly in ileum (Dudeja et al, 1996).…”

Translational repression of SLC26A3 by miR-494 in intestinal epithelial cells

“…Its altered expression and dysfunction have been associated with the pathophysiology of inflammatory and infectious diarrhea (14,32). Since miRNAs are known to contribute to the pathogenesis of intestinal inflammatory diseases including inflammatory bowel disease (7), which exhibit remarkably low DRA repression (48, 49), we hypothesized that miRNAs are involved in modulation of DRA.…”