Transepithelial HCO3- absorption is defective in renal thick ascending limbs from Na+/H+ exchanger NHE1 null mutant mice.
In the medullary thick ascending limb (MTAL) of rat kidney, inhibiting basolateral Na(+)/H(+) exchange with either amiloride or nerve growth factor (NGF) results secondarily in inhibition of apical Na(+)/H(+) exchange, thereby decreasing transepithelial HCO(3)(-) absorption. To assess the possible role of the Na(+)/H(+) exchanger NHE1 in this regulatory process, MTALs from wild-type and NHE1 knockout (NHE1(-/-)) mice were studied using in vitro microperfusion. The rate of HCO(3)(-) absorption was decreased 60% in NHE1(-/-) MTALs (15.4 +/- 0.5 pmol.min(-1).mm(-1) wild-type vs. 6.0 +/- 0.5 pmol.min(-1).mm(-1) NHE1(-/-)). Transepithelial voltage, an index of the NaCl absorption rate, did not differ in wild-type and NHE1(-/-) MTALs. Basolateral addition of 10 microM amiloride or 0.7 nM NGF decreased HCO(3)(-) absorption by 45-49% in wild-type MTALs but had no effect on HCO(3)(-) absorption in NHE1(-/-) MTALs. Inhibition of HCO(3)(-) absorption by vasopressin and stimulation by hyposmolality, both of which regulate MTAL HCO(3)(-) absorption through primary effects on apical Na(+)/H(+) exchange, were similar in wild-type and NHE1(-/-) MTALs. Thus the regulatory defect in NHE1(-/-) MTALs is specific for factors (bath amiloride and NGF) shown previously to inhibit HCO(3)(-) absorption through primary effects on basolateral Na(+)/H(+) exchange. These findings demonstrate a novel role for NHE1 in transepithelial HCO(3)(-) absorption in the MTAL, in which basolateral NHE1 controls the activity of apical NHE3. Paradoxically, a reduction in NHE1-mediated H(+) extrusion across the basolateral membrane leads to a decrease in apical Na(+)/H(+) exchange activity that reduces HCO(3)(-) absorption.
Good
David W
DW
Department of Medicine, University of Texas Medical Branch, 301 Univ. Boulevard, Galveston, TX 77555, USA. dgood@utmb.edu
Watts
Bruns A
BA
George
Thampi
T
Meyer
Jamie W
JW
Shull
Gary E
GE
D000042:Absorption; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000172:deficiency / Q000502:physiology*; D007679:Kidney Medulla / Q000378:metabolism*; D007700:Kinetics; D008138:Loop of Henle / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000494:pharmacology; D009994:Osmolar Concentration; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
D001639:Bicarbonates; D027682:Cation Transport Proteins; D008565:Membrane Proteins; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D001127:Arginine Vasopressin; D000584:Amiloride; D020932:Nerve Growth Factor