Lithium (Li⁺) is used to treat affective disorders. Developmental kidney injury after Li⁺ has been described in rat (Christensen et al. 1982). In kidney, Li⁺ inhibits glycogen synthase kinase-3b (GSK-3b) by increased phosphorylation on serine9 (s9) (Rao et al. 2005). In the present study, we hypothesised that Li+ leads to damage of the developing kidney through inhibition of GSK-3b and subsequent epithelial to mesenchymal transition (EMT). Through postnatal rat kidney development, GSK-3b mRNA was stably expressed in kidney cortex and medulla, whereas GSK-3b and pGSK-3b-s9 protein abundances in cortex decreased significantly (at P28: 15 and 10% of levels at P0, P<0.001, n=6). In kidney medulla, pGSK-3b-s9 protein abundance decreased significantly (at P28: 31% of level at P0, P<0.001, n=5–6) while total GSK-3b protein did not change with development. Immunohistochemical labelling for GSK-3b and pGSK-3b-s9 showed signals associated with the collecting duct system in adult and foetal human kidney and postnatal rat kidney. Furthermore, localisation of GSK-3b to the collecting duct system in rat kidney was assessed by PCR on microdissected segments. Li⁺ was given through the chow (50 mmol Li⁺/kg chow) to female Wistar rats with litters reduced to 8 pups through postnatal (P) P7-P29 (n=12). At P29, Li⁺-treated rat pups were polyuric and their kidneys exhibited dilated pelvis with medullary atrophy. Stereological analysis showed reduction of total kidney volume and a volume reduction of cortex, outer and inner stripe of outer medulla but not inner medulla. Li⁺-treatment increased pGSK-3b-s9 protein level significantly in pup kidney whereas total GSK-3b expression was unaltered. Lithium treatment did not alter the localisation of GSK-3b as determined by immunohistochemistry. In addition, Li⁺-treatment increased a-SMA protein level significantly whereas E-cadherin expression was unaltered. In conclusion, Li⁺-treatment disturbs normal development of the kidney medulla, increases phosphorylated, inactive GSK-3b abundance in collecting duct and leads to EMT. The data are compatible with the notion that GSK-3b activity is necessary for kidney development.

Christensen, S. et al. 1982. Acta Pathol Microbiol Immunol Scand [A] 90, 257–267. Rao, R. et al. 2005. Am J Physiol Renal Physiol 288, F642-F649.