Electroneutral sodium absorption and electrogenic anion secretion across murine small intestine are regulated in parallel

Abstract

Electrolyte transport processes of small intestinal epithelia maintain a balance between hydration of the luminal contents and systemic fluid homeostasis. Under basal conditions, electroneutral Na(+) absorption mediated by Na(+)/H(+) exchanger 3 (NHE3) predominates; under stimulated conditions, increased anion secretion mediated by CFTR occurs concurrently with inhibition of Na(+) absorption. Homeostatic adjustments to diseases that chronically affect the activity of one transporter (e.g., cystic fibrosis) may include adaptations in the opposing transport process to prevent enterosystemic fluid imbalance. To test this hypothesis, we measured electrogenic anion secretion (indexed by the short-circuit current) across NHE3-null [NHE3(-)] murine small intestine and electroneutral Na(+) absorption (by radioisotopic flux analysis) across small intestine of mice with gene-targeted disruptions of the anion secretory pathway, i.e., CFTR-null [CFTR(-)] or Na(+)-K(+)-2Cl(-) cotransporter-null [NKCC1(-)]. Protein expression of NHE3 and CFTR in the intestinal epithelia was measured by immunoblotting. In NHE3(-), compared with wild-type small intestine, maximal and bumetanide-sensitive anion secretion following cAMP stimulation was significantly reduced, and there was a corresponding decrease in CFTR protein expression. In CFTR(-) and NKCC1(-) intestine, Na(+) absorption was significantly reduced compared with wild-type. NHE3 protein expression was decreased in the CFTR(-) intestine but was unchanged in the NKCC1(-) intestine, indicating that factors independent of expression also downregulate NHE3 activity. Together, these data support the concept that absorptive and secretory processes determining NaCl and water movement across the intestinal epithelium are regulated in parallel to maintain balance between the systemic fluid volume and hydration of the luminal contents.

Luminal adenosine stimulates chloride secretion through A1receptor in mouse jejunum

“…The most abundant was A 2B receptor mRNA, which is compatible with previous reports suggesting that A 2B receptors mediate changes in gut epithelial chloride conductance (40). However, we have no direct proof that receptor protein of A 2A , A 2B , or A 3 is present in mouse jejunum, but this is likely because A 2B receptors are present on practically all cells, and A 2A and A 3 are present on vascular endothelium and/or cells of the immune system (12)(13)(14)(15)(16)24), both of which are obviously present in jejunum.…”

“…Intestinal secretion is driven by electrogenic chloride secretion by crypt cells; Cl Ϫ ions then drive Na ϩ ions by electrical coupling, and water follows by osmotic coupling. The net amount of fluid secreted is substantially greater in the small intestine than in the colon, amounting to nearly 2 liters daily in humans because it has to buffer gastric, pancreatic, and biliary secretions within its lumen; yet it is balanced by the greater absorption capacity of the small intestine even in the absence of nutrients (15). In the colon, adenosine has been shown to regulate chloride secretion through occupancy of A 2B receptors, which have been clearly demonstrated to occur on the basolateral membrane.…”

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

“…Homeostatic regulation of intestinal fluidity depends on an appropriate balance between the secretion and absorption of ions (21), with perturbations leading to either obstructions or diarrhea. A widely accepted paradigm is that fluidity is principally influenced by apical secretory mechanisms, particularly anion secretion through the CFTR.…”

“…Loss of NHE3 has been shown to cause a severe reduction in Na ϩ absorption in the intestine (22), with partial compensation occurring in the colon via upregulation of both the epithelial Na ϩ channel and the colonic H ϩ -K ϩ -ATPase (51), which is needed for maximum Na ϩ channel activity (55). Because of their opposing roles in the maintenance of intestinal fluid homeostasis (21), it seemed possible that the loss or reduction of NHE3-mediated absorption might counteract some of the pathological consequences of CFTR deficiency. To test this hypothesis, we crossed mice that were heterozygous for both the Cftr-and Nhe3-null mutations and analyzed their offspring with respect to survival rates, intestinal fluidity, histopathology and cell proliferation in the crypts.…”

News from the End of the Gut-How the Highly Segmental Pattern of Colonic HCO3- Transport Relates to Absorptive Function and Mucosal Integrity

“…37) Mice lacking either the Na ϩ /H ϩ exchanger NHE3 72) or the Cl Ϫ /HCO 3 Ϫ exchanger Slc26a3 (DRA) 46) have a significantly reduced intestinal absorptive capacity, which makes these proteins the most likely molecular correlate for NaCl absorption. NHE3 and DRA are not only expressed in the small intestine, where electroneutral NaCl absorption is the most important Na ϩ absorptive pathway in the absence of nutrients, [73][74][75] but also in the proximal colon. 76,77) The classical concept that Na ϩ /H ϩ exchange and Cl Ϫ /HCO 3 Ϫ exchange are coupled by pH changes had been established in brush border membrane vesicles.…”