title: Delayed administration of a single dose of lithium promotes recovery from AKI.
abstract: Evidence suggests that glycogen synthase kinase 3β (GSK3β) contributes to AKI; however, its role in post-AKI kidney repair remains uncertain. Here, delayed treatment with a single dose of lithium, a selective inhibitor of GSK3β and a US Food and Drug Administration-approved mood stabilizer, accelerated recovery of renal function, promoted repopulation of renal tubular epithelia, and improved kidney repair in murine models of cisplatin- and ischemia/reperfusion-induced AKI. These effects associated with reduced GSK3β activity and elevated expression of proproliferative molecules, including cyclin D1, c-Myc, and hypoxia-inducible factor 1α (HIF-1α), in renal tubular epithelia. In cultured renal tubular cells, cisplatin exposure led to transient repression of GSK3β activity followed by a prolonged upregulation of activity. Rescue treatment with lithium inhibited GSK3β activity, enhanced nuclear expression of cyclin D1, c-Myc, and HIF-1α, and boosted cellular proliferation. Similarly, ectopic expression of a kinase-dead mutant of GSK3β enhanced the expression of cyclin D1, c-Myc, and HIF-1α and amplified cellular proliferation after cisplatin injury, whereas forced expression of a constitutively active mutant of GSK3β abrogated the effects of lithium. Mechanistically, GSK3β colocalized and physically interacted with cyclin D1, c-Myc, and HIF-1α in tubular cells. In silico analysis revealed that cyclin D1, c-Myc, and HIF-1α harbor putative GSK3β consensus phosphorylation motifs, implying GSK3β-directed phosphorylation and subsequent degradation of these molecules. Notably, cotreatment with lithium enhanced the proapoptotic effects of cisplatin in cultured colon cancer cells. Collectively, our findings suggest that pharmacologic targeting of GSK3β by lithium may be a novel therapeutic strategy to improve renal salvage after AKI.
authors.affiliation: Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Hui
authors.initials: H
authors.lastname: Bao
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.forename: Lance
authors.initials: L
authors.lastname: Dworkin
authors.forename: Ai
authors.initials: A
authors.lastname: Peng
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008094:Lithium / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D012038:Regeneration / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D018692:Antimanic Agents; D000970:Antineoplastic Agents; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002945:Cisplatin