TY - JOUR
T1 - Luminal Osmolarity Downregulates Gene Expression of Na+/H+ Exchanger (NHE3) in Rat Colon Mucosa
AU - Doble, Marc A.
AU - Tola, Vicky B.
AU - Cima, Robert R.
AU - Zinner, Michael J.
AU - Klein, Michael A.
AU - Soybel, David I.
N1 - Funding Information:
The role of Na+/H ÷ exchangers in epithelial sodium absorption has been extensively studied. In their normal mode of operation, these proteins mediate the exchange ofintracellular H ÷ for extracellular Na + in a one-to-one ratio. Na+/H ÷ exchangers function to maintain intracellular pH and aid in cell volume regulation and cell proliferation. To date, five different isoforms of the NHE have been found. 1"11 NHE1 has been found, with few exceptions, in all cells, and has been localized to the basolateral membrane of epithelial cells) In contrast, NHE2 and NHE3 have been localized to the apical membranes of diverse epithelial cells. With the use of Northern blot analysis, NHE2 has been found in the kidney medulla and cortex, liver, stomach, duodenum, ileum, jejunum, colon, and adrenal gland. 4,s,~2 The functional role of NHE2 in the intestine has yet to be determined. With respect to the NHE3 isoform, high levels of mRNA have been found in the kidney medulla and cortex, store- ach, jejunum, ileum, and colon. 7,9,12 Functional studies using transgenic knockout models have shown serious absorptive defects in mice lacking the NHE3 exchanger. 13 It has also been revealed that aldosterone, secreted during periods of salt deprivation, increases Na ÷ uptake by increasing cellular NHE3 expression in the colon. 14 From these and other studies, it is believed that NHE3 is the dominant Na÷/H ÷ exchanger in the intestine and colon. 6-9,12,15,16 NHE4 has been localized to the basolateral membranes of epithelial cells in the stomach and kidney, as well as nonpolar cells in the brain, uterus, and skeletal muscle) Its exact function has not yet been determined. With the exception of NHE4, all Na+/H + exchangers are inhibited by the diuretic amiloride and are selectively inhibited by several new amiloride derivatives. 17 Despite considerable investigation of the neurohumoral and cellular mechanisms that regulate expression and function of NHE isoforms, there is lit- From the Department of Surgery (M.A.D., R.R.C., M.J.Z., and D.I.S.), Brigham and Women's Hospital, and the Departments of Surgery (M.A.D., V.B.T., R.R.C., M.J.Z., and D.I.S.) and Pathology (M.A.K.), West RoxburyV eterans Administration Medical Center, Harvard Medical School, Boston, Mass. Supported by the Brigham Surgical Group Foundation and National Institutes of Health Award RO1-DK 44571 (D.I.S.). Reprint requests: David I. Soybel, M.D., Department of Surgery/112, West Roxbury Veterans Administration Medical Center, 1400 VFW Parkway, West Roxbury,M A 02132. e-mail: [email protected]
PY - 2000
Y1 - 2000
N2 - Water-coupled Na+ absorption in the colon is mediated principally by Na+/H+ exchange (isoforms NHE2 and NHE3). To determine whether luminal ion composition or osmolarity influences NHE expression in colon mucosa, two groups (n = 6 in each) of adult male Sprague-Dawley rats underwent sham laparotomy or loop ileostomy. In these studies, diversion did not markedly alter mRNA levels for NTHE2, NHE3, or Na+/K+, at 8 or 21 days, indicating that loss of luminal volume does not alter NHE gene expression. To evaluate the effects of specific luminal components, we infused equal volumes of half-normal (154 mOsm) or iso-osmolar (308 mOsm) solutions of saline and mannitol into the diverted colon. All solutions elicited significant (45% to 60%; P <0.05) decreases in mRNA levels for NHE3, with iso-osmolar mannitol eliciting the greatest changes. Decreases in NHE2 and Na+/K+ mRNA levels were observed following these infusions but were not as marked as the changes for NHE3. These findings suggest that (1) loss of luminal Na+ is not, in itself, a signal that regulates NHE expression and (2) infusion of any solute, including Na+ itself, provides a signal to downregulate expression of NHE3 in colon mucosa.
AB - Water-coupled Na+ absorption in the colon is mediated principally by Na+/H+ exchange (isoforms NHE2 and NHE3). To determine whether luminal ion composition or osmolarity influences NHE expression in colon mucosa, two groups (n = 6 in each) of adult male Sprague-Dawley rats underwent sham laparotomy or loop ileostomy. In these studies, diversion did not markedly alter mRNA levels for NTHE2, NHE3, or Na+/K+, at 8 or 21 days, indicating that loss of luminal volume does not alter NHE gene expression. To evaluate the effects of specific luminal components, we infused equal volumes of half-normal (154 mOsm) or iso-osmolar (308 mOsm) solutions of saline and mannitol into the diverted colon. All solutions elicited significant (45% to 60%; P <0.05) decreases in mRNA levels for NHE3, with iso-osmolar mannitol eliciting the greatest changes. Decreases in NHE2 and Na+/K+ mRNA levels were observed following these infusions but were not as marked as the changes for NHE3. These findings suggest that (1) loss of luminal Na+ is not, in itself, a signal that regulates NHE expression and (2) infusion of any solute, including Na+ itself, provides a signal to downregulate expression of NHE3 in colon mucosa.
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U2 - 10.1016/S1091-255X(00)80097-9
DO - 10.1016/S1091-255X(00)80097-9
M3 - Article
C2 - 11077330
AN - SCOPUS:0034264184
SN - 1091-255X
VL - 4
SP - 531
EP - 535
JO - Journal of Gastrointestinal Surgery
JF - Journal of Gastrointestinal Surgery
IS - 5
ER -