Altered expression of renal AQPs and Na(+) transporters in rats with lithium-induced NDI.
Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H exchanger (NHE3), type 2 Na-Pi cotransporter (NaPi-2), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), and thiazide-sensitive Na-Cl cotransporter (TSC) were examined in rats treated with Li orally for 4 wk: protocol 1, high doses of Li (high Na(+) intake), and protocol 2, low doses of Li (identical food and normal Na(+) intake in Li-treated and control rats). Both protocols resulted in severe polyuria. Semiquantitative immunoblotting revealed that whole kidney abundance of AQP2 was dramatically reduced to 6% (protocol 1) and 27% (protocol 2) of control levels. In contrast, the abundance of AQP1 was not decreased. Immunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked increase in urinary Na(+) excretion in both protocols. However, the expression of several major Na(+) transporters in the proximal tubule, loop of Henle, and distal convoluted tubule was unchanged in protocol 2, whereas in protocol 1 significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 expression was associated with chronic Li treatment. In conclusion, severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria. In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na(+) transporters do not participate in the development of Li-induced polyuria.
Kwon
T H
TH
Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, United Kingdom.
Laursen
U H
UH
Marples
D
D
Maunsbach
A B
AB
Knepper
M A
MA
Frokiaer
J
J
Nielsen
S
S
D000818:Animals; D051398:Aquaporin 1; D051399:Aquaporin 2; D051400:Aquaporin 3; D051403:Aquaporin 6; D020346:Aquaporins / Q000096:biosynthesis* / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism; D003919:Diabetes Insipidus / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism*; D004231:Diuresis / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007671:Kidney Concentrating Ability / Q000187:drug effects / Q000502:physiology; D007679:Kidney Medulla / Q000378:metabolism / Q000648:ultrastructure; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000648:ultrastructure; D008094:Lithium / Q000009:adverse effects*; D008297:Male; D016253:Microscopy, Immunoelectron; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000096:biosynthesis / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D028021:Sodium-Potassium-Chloride Symporters; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D014867:Water / Q000378:metabolism
C496022:Aqp1 protein, rat; C496025:Aqp2 protein, rat; C496029:Aqp3 protein, rat; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D002352:Carrier Proteins; D011955:Receptors, Drug; C578876:Slc12a3 protein, rat; C000613387:Slc9a3 protein, rat; D049992:Sodium Chloride Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D028021:Sodium-Potassium-Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D014867:Water; D051398:Aquaporin 1; D051400:Aquaporin 3; D008094:Lithium; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase