Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins.
ACE.2 mice lack all tissue angiotensin-converting enzyme (ACE) but have 33% of normal plasma ACE activity. They exhibit the urine-concentrating defect and hyperkalemia present in mice that lack all ACE, but in contrast to the complete knockout, ACE.2 mice have normal medullary histology and creatinine clearance. To explore the urine-concentrating defect in ACE.2 mice, renal medullary transport proteins were analyzed using Western blot analysis. In the inner medulla, UT-A1, ClC-K1, and aquaporin-1 (AQP1) were significantly reduced to 28 +/- 5, 6 +/- 6, and 39 +/- 5% of the level in wild-type mice, respectively, whereas AQP2 and UT-B were unchanged. In the outer medulla, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2/BSC1) and AQP1 were significantly reduced to 56 +/- 11 and 29 +/- 6%, respectively, whereas Na(+)-K(+)-ATPase, UT-A2, UT-B, and AQP2 were unchanged, and renal outer medullary potassium channel was significantly increased to 711 +/- 187% of the level in wild-type mice. The abnormal expression of these transporters was similar in ACE.2 mice backcrossed onto a C57BL/6 or a Swiss background and was not rescued by ANG II infusion. We conclude that the urine-concentrating defect in ACE.2 mice is associated with, and may result from, downregulation of some or all of these key urea, salt, and water transport proteins.
Klein
Janet D
JD
Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Le Quach
D
D
Cole
Justin M
JM
Disher
Kevin
K
Mongiu
Anne K
AK
Wang
Xiaodan
X
Bernstein
Kenneth E
KE
Sands
Jeff M
JM
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D051398:Aquaporin 1; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000032:analysis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis*; D018118:Chloride Channels / Q000032:analysis; D006863:Hydrogen-Ion Concentration; D007671:Kidney Concentrating Ability; D007672:Kidney Cortex / Q000737:chemistry; D007679:Kidney Medulla / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009994:Osmolar Concentration; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D014556:Urine; D000096982:Urea Transporters
D000804:Angiotensin II; D051398:Aquaporin 1; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D002352:Carrier Proteins; D018118:Chloride Channels; D026901:Membrane Transport Proteins; D007703:Peptidyl-Dipeptidase A; D028021:Sodium-Potassium-Chloride Symporters; D000254:Sodium-Potassium-Exchanging ATPase; D000096982:Urea Transporters; C496021:Aqp1 protein, mouse; C496024:Aqp2 protein, mouse; C489933:Clcnka protein, mouse; C452857:urea transporter B, mouse