Lithium induces aerobic glycolysis and glutaminolysis in collecting duct principal cells.
Am J Physiol Lung Cell Mol Physiol 2017 Oct 25 [Epub ahead of print]
Lithium, given to bipolar disorder patients, causes nephrogenic diabetes insipidus (Li-NDI), a urinary concentrating defect. Li-NDI is due to downregulation of principal cell AQP2 expression, which coincides with principal cell proliferation. The metabolic effect of lithium on principal cells, however, is unknown and investigated here. Earlier, we have shown that the carbonic anhydrase (CA) inhibitor acetazolamide attenuated Li-induced downregulation in mouse collecting duct (mpkCCD) cells. Of the eight CAs present in mpkCCD cells, siRNA and drug treatments showed that downregulation of CA9 and to some extent CA12 attenuated Li-induced AQP2 downregulation. Moreover, lithium induced cell proliferation and increased the secretion of lactate. Lithium also increased urinary lactate levels in wildtype mice that developed Li-NDI, but not in lithium-treated mice lacking ENaC, the principal cell entry site for lithium. Inhibition of aerobic glycolysis with 2-deoxyglucose (2DG) attenuated lithium-induced AQP2 downregulation in mpkCCD cells, but did not attenuate Li-NDI in mice. Interestingly, NMR analysis demonstrated that lithium also increased the urinary succinate, fumarate, citrate, and NH4+ levels, which were, in contrast to lactate, not decreased by 2DG. Together, our data reveal that lithium induces aerobic glycolysis and glutaminolysis in principal cells and that inhibition of aerobic glycolysis, but not the glutaminolysis, does not attenuate Li-NDI. Am J Physiol Lung Cell Mol Physiol 2017 Oct 25 [Epub ahead of print]
Alsady, Mohammad; de Groot, Theun; Kortenoeven, Marleen Louise Adriënne; Carmone, Claudia; Neijman, Kim; Bekkenkamp-Grovenstein, Melissa; Engelke, Udo; Wevers, Ron; Baumgarten, Ruben; Korstanje, Ron; and Deen, Peter M T, "Lithium induces aerobic glycolysis and glutaminolysis in collecting duct principal cells." (2017). Faculty Research Ahead of Print. 34.