Hyposmolality stimulates apical membrane Na(+)/H(+) exchange and HCO(3)(-) absorption in renal thick ascending limb.
The regulation of epithelial Na(+)/H(+) exchangers (NHEs) by hyposmolality is poorly understood. In the renal medullary thick ascending limb (MTAL), transepithelial bicarbonate (HCO(3)(-)) absorption is mediated by apical membrane Na(+)/H(+) exchange, attributable to NHE3. In the present study we examined the effects of hyposmolality on apical Na(+)/H(+) exchange activity and HCO(3)(-) absorption in the MTAL of the rat. In MTAL perfused in vitro with 25 mM HCO(3)(-) solutions, decreasing osmolality in the lumen and bath by removal of either mannitol or sodium chloride significantly increased HCO(3)(-) absorption. 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. Hyposmolality increased apical Na(+)/H(+) exchange activity over the pH(i) range 6.5-7.5 due to an increase in V(max). Pretreatment with either tyrosine kinase inhibitors or with the tyrosine phosphatase inhibitor molybdate completely blocked stimulation of HCO(3)(-) absorption by hyposmolality. These results demonstrate that hyposmolality increases HCO(3)(-) absorption in the MTAL through a novel stimulation of apical membrane Na(+)/H(+) exchange and provide the first evidence that NHE3 is regulated by hyposmotic stress. Stimulation of apical Na(+)/H(+) exchange activity in renal cells by a decrease in osmolality may contribute to such pathophysiological processes as urine acidification by diuretics, diuretic resistance, and renal sodium retention in edematous states.
Watts
B A
BA
Department of Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Good
D W
DW
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones; D001639:Bicarbonates / Q000378:metabolism*; D004791:Enzyme Inhibitors; D005665:Furosemide / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008138:Loop of Henle / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000378:metabolism; D009994:Osmolar Concentration; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D012965:Sodium Chloride / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology
D016227:Benzoquinones; D001639:Bicarbonates; D004791:Enzyme Inhibitors; D006146:Guanidines; D047029:Lactams, Macrocyclic; D011809:Quinones; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D017828:Rifabutin; D008353:Mannitol; D012965:Sodium Chloride; C020754:herbimycin; D000584:Amiloride; D005665:Furosemide; D019833:Genistein; D011505:Protein-Tyrosine Kinases