Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3␤-positive epithelium. It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3␤ (GSK-3␤). GSK-3␤ immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult

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... human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3␤ (pGSK-3␤) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7-28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithiumtreated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3␤ and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3␤immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithiumtreated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3␤-, and pGSK-3␤-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3␤, proliferation, and microcysts. development; cyst; proliferation; medulla, collecting duct LITHIUM IS USED FOR PROPHYLAXIS and treatment of affective disorders and is often given for years, but its use is associated with a range of renal functional and structural adverse effects (3). In a pioneering study from 1982, lithium precipitated tissue injury, decreased the glomerular filtration rate (GFR), and urine concentrating ability when administered from birth through 8 postnatal weeks, while it had no effect on the prenatal kidney (28). Lithium discontinuation did not resolve functional or structural injury (10, 28). In contrast, long-term lithium treatment of the adult rat kidney