Specific deletion of glycogen synthase kinase-3β in the renal proximal tubule protects against acute nephrotoxic injury in mice.

Howard C, Tao S, Yang HC, Fogo AB, Woodgett JR, Harris RC, Rao R
Kidney Int. 2012 82 (9): 1000-9

PMID: 22785175 · PMCID: PMC3472082 · DOI:10.1038/ki.2012.239

Renal proximal tubular damage and repair are hallmarks of acute kidney injury. As glycogen synthase kinase-3β (GSK3β) is an important cellular regulator of survival and proliferation, we determined its role during injury and recovery of proximal tubules in a mercuric chloride-induced nephrotoxic model of acute kidney injury. Renal proximal tubule-specific GSK3β knockout mice exposed to mercuric chloride had improved survival and renal function compared to wild-type mice. Apoptosis, measured by TUNEL staining, Bax activation, and caspase 3 cleavage, was reduced in the knockout mice. The restoration of renal structure, function, and cell proliferation was also accelerated in the GSK3β knockout mice. This enhanced repair, evidenced by increased Ki-67 and BRDU staining, along with increased cyclin D1 and c-myc levels, was recapitulated by treatment of wild-type mice with the small-molecule GSK3 inhibitor TDZD-8 following injury. This confirmed that hastened repair in the knockout mice was not merely due to lower initial injury levels. Thus, inhibition of GSK3β prior to nephrotoxic insult protects from renal injury. Such treatment after acute kidney injury may accelerate repair and regeneration.

MeSH Terms (18)

Acute Disease Acute Kidney Injury Animals Anti-Infective Agents, Local Apoptosis Cell Proliferation Disease Models, Animal Female Gene Deletion Glycogen Synthase Kinase 3 Glycogen Synthase Kinase 3 beta Kaplan-Meier Estimate Kidney Tubules, Proximal Mercuric Chloride Mice Mice, Inbred C57BL Mice, Knockout Thiadiazoles

Connections (2)

This publication is referenced by other Labnodes entities: