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Chloroquine Attenuates Lithium-induced NDI and Proliferation of Renal Collecting Duct Cells.

Lithium is widely used in psychiatry as golden standard for more than 60 years due to its effectiveness. However, its adverse effect has been limiting its long-term use in clinic. About 40% patients taking lithium develop nephrogenic diabetes insipidus (NDI). Lithium can also induce proliferation of collecting duct cells, leading to microcysts formation in the kidney. Lithium was considered as autophagy inducer which may contribute to the therapeutic benefit of neuropsychiatric disorders. Thus, we hypothesized that autophagy may play a role in lithium induced kidney nephrotoxicity. To address our hypothesis, we fed mice with lithium-containing diet with chloroquine (CQ)-an autophagy inhibitor concurrently. Lithium-treated mice presented enhanced autophagy activity in kidney cortex and medulla. CQ treatment significantly ameliorated lithium-induced polyuria, polydipsia, natriuresis and kaliuresis accompanied with attenuated downregulation of AQP2 and NKCC2 protein. The protective effect of CQ on AQP2 protein abundance was confirmed in cultured cortical collecting duct cells. In addition, we found lithium-induced proliferation of collecting duct cells was also suppressed by CQ detected by PCNA staining. Moreover, both p-mTOR and β-catenin expression which has been reported to be increased by lithium and associated with cell proliferation were reduced by CQ. Taken together, our study demonstrated that chloroquine protected against lithium-induced NDI and collecting duct cell proliferation possibly through inhibiting autophagy.