Altered expression of renal AQPs and Na+ transporters in rats with lithium-induced NDI

Lithium (Li) treatment is often associated with nephrogenic diabetes insipi dus (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 N a+ intake), and protocol 2, low doses of Li (identical food and normal Naintake in Li-treated and control rats). Both protocols resulted in severe p olyuria. Semiquantitative immunoblotting revealed that whole kidney abundan ce 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. I mmunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked i ncrease in urinary Na+ excretion in both protocols. However, the expression of several major Na+ transporters in the proximal tubule, loop of Henle, a nd distal convoluted tubule was unchanged in protocol 2, whereas in protoco l 1 significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 exp ression was associated with chronic Li treatment. In conclusion, severe dow nregulation 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.