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Gene Review

Slc9a3  -  solute carrier family 9, subfamily A (NHE3...

Rattus norvegicus

Synonyms: NHE-3, Na(+)/H(+) exchanger 3, Nhe3, Sodium/hydrogen exchanger 3, Solute carrier family 9 member 3
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Disease relevance of Slc9a3

  • CONCLUSION: In the renal proximal tubule, chronic metabolic acidosis induces an increase in preproET-1 expression, providing a mechanism for autocrine regulation of proximal tubule NHE3 activity [1].
  • Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome [2].
  • In conclusion, increased sodium reabsorption might be associated with a shift of NHE3 from an inactive pool to an active pool, thus contributing to sodium retention in a state of proteinuria [2].
  • Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity [3].
  • The purpose of this study was to analyze the long-term regulation of NHE3 during alkalosis induced by dietary NaHCO(3) loading and changes in NaCl intake [4].

High impact information on Slc9a3

  • Given that partially purified Pyk2 can be activated by acid in a cell-free system, Pyk2 may serve as the pH sensor that initiates the acid-regulated signaling cascade involved in NHE3 regulation [5].
  • Transfection of OKP cells with dominant-negative pyk2(K457A) or small interfering pyk2 duplex RNA blocked acid activation of NHE3, while neither had an effect on glucocorticoid activation of NHE3 [5].
  • In addition, pyk2(K457A) blocked acid activation of c-Src kinase, which is also required for acid regulation of NHE3 [5].
  • The responses to lumen addition of the inhibitors ethylisopropyl amiloride, amiloride, or HOE 694 are consistent with hyposmotic stimulation of apical NHE3 activity and provide no evidence for a role for apical NHE2 in HCO(3)(-) absorption [6].
  • In the renal medullary thick ascending limb (MTAL), transepithelial bicarbonate (HCO(3)(-)) absorption is mediated by apical membrane Na(+)/H(+) exchange, attributable to NHE3 [6].

Chemical compound and disease context of Slc9a3

  • The activity of the apical membrane Na+/H+ exchanger NHE3 isoform of renal or intestinal epithelial cells is chronically regulated by a wide variety of stimuli, including acidosis, cAMP, glucocorticoids, and thyroid hormone [7].
  • The regulation of the cortical Na/H exchanger NHE3, the main pathway for Na reabsorption in the proximal tubule (PT), was investigated in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome [2].
  • Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension [8].
  • (2) In KD, NHE-3 expression did not decrease despite the presence of metabolic alkalosis, in agreement with the unchanged HCO3- absorptive capacity of Henle's loop [9].
  • The dopamine D(3) receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D(2)-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580 [10].

Biological context of Slc9a3

  • These mapping data also indicate that the Slc9a3 gene, encoding the Na+/H+ exchanger 3, is an unlikely candidate for the blood pressure loci assigned to rat Chr 1 [11].
  • We conclude that regulation of NHE-3 by PKA in vivo involves complex mechanisms, which include phosphorylation of Ser-552 and Ser-605 [12].
  • Genomic organization and glucocorticoid transcriptional activation of the rat Na+/H+ exchanger Nhe3 gene [7].
  • The glucocorticoid responsiveness of the Nhe3 gene was assessed by fusing its 5' regulatory region to the firefly luciferase reporter gene and then by measuring the expression of the chimeric gene in transiently transfected renal epithelial OK and LLC-PK1 cells [7].
  • We investigated whether the reduction of renal mass is associated with alterations in LOH bicarbonate transport coupled to changes in NHE-3 gene expression and in vivo activity [13].

Anatomical context of Slc9a3

  • Whether this occurs through enhanced expression and/or function of the brush-border Na+/H+ exchangers (NHE)2 and NHE3 is unknown [14].
  • Intracellular pH measurements in parietal cells conducted in omeprazole-pretreated superfused gastric glands showed an Na+-dependent proton extrusion pathway that was inhibited both by low concentrations of EIPA and by the NHE-3 specific inhibitor S3226 [15].
  • Glucocorticoid treatment significantly increased the luciferase activity of the chimeric gene in both cell lines, thereby indicating that glucocorticoid regulation of Nhe3 is mediated primarily by a transcriptional mechanism [7].
  • There was no expression of NHE-2, NHE-3, or NHE-4 in SHR and WKY aortas or in cultured vascular smooth muscle cells from SHR and WKY aortas [16].
  • After 5-min hypertension, 20% of total NHE3 protein, assayed by immunoblot, redistributed from low-density apical membranes to middensity membranes enriched in intermicrovillar cleft markers; by 30 min, a similar percentage shifted to heavier density membranes containing markers of endosomes [3].

Associations of Slc9a3 with chemical compounds

  • We suggest that overexpression of colonic H+-K+-ATPase in the early phase of renal reperfusion injury may be responsible for compensatory reabsorption of increased HCO3- load resulting from suppression of NHE-3 [17].
  • Furthermore, l-NAME infusion in aldosterone-treated rats markedly decreased both NHE3 and NKCC2 protein abundance, without changes in the corresponding mRNA levels [18].
  • BACKGROUND: The bulk of bicarbonate reabsorption along the loop of Henle (LOH) is localized at the level of the thick ascending limb (TAL) and is mainly dependent on the presence of luminal Na+-H+ exchanger (NHE-3) [13].
  • There were no differences for the sodium hydrogen exchanger (NHE3), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2 or BSC1), the type II sodium-phosphate cotransporter (NaPi-2), or the alpha-subunit of ENaC [19].
  • In previous studies examining the role of glucocorticoids and thyroid hormone on the maturation of the Na(+)/H(+) antiporter (NHE3), we found attenuation in the maturational increase in proximal tubule apical Na(+)/H(+) antiporter activity but no change in NHE3 mRNA abundance in either glucocorticoid-deficient or hypothyroid rats [20].

Regulatory relationships of Slc9a3

  • Role of c-SRC and ERK in acid-induced activation of NHE3 [21].
  • To determine the role of c-Src in acid-induced NHE3 activation, cells were transfected with vector alone or a dominant negative c-Src (c-SrcK295M) [21].
  • Inhibition of MEK with PD98059 inhibited activation of NHE3 by acid incubation [21].
  • In the MTAL, apical NHE3 mediates H(+) secretion necessary for HCO(3)(-) absorption; basolateral NHE1 influences HCO(3)(-) absorption by regulating apical NHE3 activity [22].

Other interactions of Slc9a3

  • An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3 [1].
  • After 80% resection, increases in NHE2 and NHE3 became evident in proximal colon [23].
  • Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO [18].
  • CONCLUSIONS: These findings demonstrate a differential expression of NHE-1 and NHE-3 isoforms which is dependent on the rise in BP, PGE(2) or TXB(2) in the long-term treatment group, but not in the short-term treatment group [24].
  • In ANG II-clamped rats, acute hypertension also provoked disappearance of NHE3 from the apical membranes (27 +/- 2% decrease of total), but NHE3 was shifted to membranes enriched in intermicrovillar cleft and dense apical tubules (step 1) rather than endosomal/lysosomal membranes (step 2) [8].

Analytical, diagnostic and therapeutic context of Slc9a3

  • Western blot analysis and immunohistochemistry showed expression of NHE-3 in rat stomach colocalizing the protein in parietal cells together with the beta-subunit of the H(+)-K(+)-ATPase [15].
  • AMV NHE3 protein abundance assessed by Western blot analysis was unaffected during changes in NaCl intake [4].
  • Western blot analysis of brush-border membranes and Northern blot analysis of cortex RNA showed that NHE3 protein abundance and NHE3 mRNA were greatly enhanced 4 and 24 h after UNX in relation to the sham kidney [25].
  • The most striking changes followed 30 minutes of occlusion and 12 hours of reperfusion and involved the mRNA for NHE-3 (involved in HCO3- reabsorption in proximal tubule and thick limb) and colonic H+-K+-ATPase (involved in HCO3- reabsorption in collecting duct) [17].
  • NHE-3 gene expression was quantified by competitive PCR using an internal standard of cDNA that differed from the wild-type NHE-3 by a deletion of 76 bp [13].


  1. An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3. Licht, C., Laghmani, K., Yanagisawa, M., Preisig, P.A., Alpern, R.J. Kidney Int. (2004) [Pubmed]
  2. Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. Besse-Eschmann, V., Klisic, J., Nief, V., Le Hir, M., Kaissling, B., Ambühl, P.M. J. Am. Soc. Nephrol. (2002) [Pubmed]
  3. Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Yang, L., Leong, P.K., Chen, J.O., Patel, N., Hamm-Alvarez, S.F., McDonough, A.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  4. Rat proximal NHE3 adapts to chronic acid-base disorders but not to chronic changes in dietary NaCl intake. Eladari, D., Leviel, F., Pezy, F., Paillard, M., Chambrey, R. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  5. Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3. Li, S., Sato, S., Yang, X., Preisig, P.A., Alpern, R.J. J. Clin. Invest. (2004) [Pubmed]
  6. Hyposmolality stimulates apical membrane Na(+)/H(+) exchange and HCO(3)(-) absorption in renal thick ascending limb. Watts, B.A., Good, D.W. J. Clin. Invest. (1999) [Pubmed]
  7. Genomic organization and glucocorticoid transcriptional activation of the rat Na+/H+ exchanger Nhe3 gene. Kandasamy, R.A., Orlowski, J. J. Biol. Chem. (1996) [Pubmed]
  8. Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension. Leong, P.K., Yang, L.E., Holstein-Rathlou, N.H., McDonough, A.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  9. Expression of rat thick limb Na/H exchangers in potassium depletion and chronic metabolic acidosis. Laghmani, K., Richer, C., Borensztein, P., Paillard, M., Froissart, M. Kidney Int. (2001) [Pubmed]
  10. Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event. Pedrosa, R., Gomes, P., Hopfer, U., Jose, P.A., Soares-da-Silva, P. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  11. Rat chromosome 1: regional localization of seven genes (Slc9a3, Srd5a1, Esr, Tcp1, Grik5, Tnnt3, Jak2) and anchoring of the genetic linkage map to the cytogenetic map. Szpirer, C., Szpirer, J., Tissir, F., Stephanova, E., Vanvooren, P., Kurtz, T.W., Iwai, N., Inagami, T., Pravenec, M., Kren, V., Klinga-Levan, K., Levan, G. Mamm. Genome (1997) [Pubmed]
  12. Acute inhibition of Na/H exchanger NHE-3 by cAMP. Role of protein kinase a and NHE-3 phosphoserines 552 and 605. Zhao, H., Wiederkehr, M.R., Fan, L., Collazo, R.L., Crowder, L.A., Moe, O.W. J. Biol. Chem. (1999) [Pubmed]
  13. Bicarbonate reabsorption and NHE-3 expression: abundance and activity are increased in Henle's loop of remnant rats. Capasso, G., Rizzo, M., Pica, A., Di Maio, F.S., Moe, O.W., Alpern, R.J., De Santo, N.G. Kidney Int. (2002) [Pubmed]
  14. Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function. Lucioni, A., Womack, C., Musch, M.W., Rocha, F.L., Bookstein, C., Chang, E.B. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  15. Demonstration of a functional apical sodium hydrogen exchanger in isolated rat gastric glands. Kirchhoff, P., Wagner, C.A., Gaetzschmann, F., Radebold, K., Geibel, J.P. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  16. Na(+)-H+ exchanger expression in vascular smooth muscle of spontaneously hypertensive and Wistar-Kyoto rats. Lucchesi, P.A., DeRoux, N., Berk, B.C. Hypertension (1994) [Pubmed]
  17. Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Wang, Z., Rabb, H., Craig, T., Burnham, C., Shull, G.E., Soleimani, M. Kidney Int. (1997) [Pubmed]
  18. Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO. Turban, S., Wang, X.Y., Knepper, M.A. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  19. Increased renal Na-K-ATPase, NCC, and beta-ENaC abundance in obese Zucker rats. Bickel, C.A., Verbalis, J.G., Knepper, M.A., Ecelbarger, C.A. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  20. Maturation of the Na+/H+ antiporter (NHE3) in the proximal tubule of the hypothyroid adrenalectomized rat. Gupta, N., Dwarakanath, V., Baum, M. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  21. Role of c-SRC and ERK in acid-induced activation of NHE3. Tsuganezawa, H., Sato, S., Yamaji, Y., Preisig, P.A., Moe, O.W., Alpern, R.J. Kidney Int. (2002) [Pubmed]
  22. Nongenomic regulation by aldosterone of the epithelial NHE3 Na(+)/H(+) exchanger. Good, D.W., George, T., Watts, B.A. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  23. Region-specific adaptation of apical Na/H exchangers after extensive proximal small bowel resection. Musch, M.W., Bookstein, C., Rocha, F., Lucioni, A., Ren, H., Daniel, J., Xie, Y., McSwine, R.L., Rao, M.C., Alverdy, J., Chang, E.B. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  24. Altered expression of Na(+)/H(+) exchanger isoforms 1 and 3 in clipped and unclipped kidneys of a 2-kidney-1-clip Goldblatt model of hypertension. Khan, I., Al-Qattan, K.K., Alnaqeeb, M.A., Ali, M. Nephron (2002) [Pubmed]
  25. Upregulation of NHE3 is associated with compensatory cell growth response in young uninephrectomized rats. Girardi, A.C., Rocha, R.O., Britto, L.R., Rebouças, N.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
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