1 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 Det Sundhedsvidenskabelige Fakultet, SDU3 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU4 Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU5 Københavns Universitet6 OUH7 Kardiovaskulær og Renal Forskning, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU8 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
Lithium is reabsorbed by distal nephron segments in sodium depleted states. It was hypothesized that lithium causes permanent injury to the developing kidney particularly in the sodium-retaining phase around weaning through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β and pGSK-3β was investigated in a developing series of rat kidney cortex and medulla. Li+ was given to female wistar rats with litters through food pellets at postnatal (P) days 7-28. In human fetal and adult kidney the expression of GSK-3β was examined and also a kidney from a lithium treated patient was investigated. GSK-3β was associated with connecting tubule and collecting ducts in developing and adult human and rat kidney. Renal abundance of inactive, serine9 phosphorylated GSK-3β protein decreased significantly with postnatal development. At P28, plasma Li+ in offspring was 1.0 mmol/L. Kidneys exhibited dilated distal nephron segments with occasional cysts. Quantitative stereological analysis showed reduced total kidney volume, cortex and outer medulla volumes while inner medulla volume was not affected. Li+ increased pGSK-3β protein abundance in kidney and pGSK-3β-immunopositive cells was associated with cortical collecting ducts. Li+ increased cell proliferation while E-cadherin abundance and localization was not changed. After 6 weeks of lithium discontinution, male rats exhibited attenuated urine concentration capacity (2747 vs. 2126 mOsm/kg H2O), with no difference in AQP2 abundance. Human kidney from chronic lithium treated patient showed cortical cysts that were GSK-3β and pGSK-3β-immunopositive. In conclusion we find that postnatal kidney development is associated with increased abundance of active, dephosphorylated GSK-3β in distal nephron segments. Lithium causes proliferation, structural injury and increases inactive pGSK-3β abundance in these segments. The data are compatible with epithelial entry of lithium and a causal role for GSK-3β in postnatal developing cortical collecting duct epithelium.