Specific deletion of glycogen synthase kinase-3β in the renal proximal tubule protects against acute nephrotoxic injury in mice.
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.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Christiana
C
Howard
Shixin
S
Tao
Hai-Chun
HC
Yang
Agnes B
AB
Fogo
James R
JR
Woodgett
Raymond C
RC
Harris
Reena
R
Rao
D000208:Acute Disease; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D053208:Kaplan-Meier Estimate; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000502:physiology*; D008627:Mercuric Chloride / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013830:Thiadiazoles / Q000494:pharmacology
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000891:Anti-Infective Agents, Local; D013830:Thiadiazoles; D008627:Mercuric Chloride; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3