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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)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT
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.

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Cyclin D1 and c-myc levels are higher in KO Kidneysa) Western blot analysis and b, c) quantitation of band density for protein levels of cyclin D1, c-myc and β-catenin. Fig 6d & 6c based on two time course studies**, P<0.001. ***, P<0.0001. Data= mean ± SD
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Figure 6: Cyclin D1 and c-myc levels are higher in KO Kidneysa) Western blot analysis and b, c) quantitation of band density for protein levels of cyclin D1, c-myc and β-catenin. Fig 6d & 6c based on two time course studies**, P<0.001. ***, P<0.0001. Data= mean ± SD

Mentions: To examine the mechanism for the higher rate of proliferation in the KO mice, protein levels of the pro-proliferative factors, cyclin D1, c-myc and β-catenin, known to be regulated by GSK3β were measured. Cyclin D1 and c-myc levels in the kidney cortex were markedly upregulated in KO mice compared to WT mice, especially on days 1–4 (Fig 6a). Interestingly, cyclin D1 levels decreased by day 6 in the KO mice, while in the WT mice, the highest cyclin D1 levels were observed on days 6 and 8 (Fig 6b). c-myc levels were significantly higher in KO mice on day 3, 4 and 6 compared to that in WT mice (Fig 6c). β-catenin levels did not differ significantly between the WT and KO groups. These results indicated an accelerated rate of proliferation in KO mice when compared to WT mice. Examination of renal fibrosis by sirius red staining, a marker of collagen, revealed no significant difference between the WT and KO mice 8 days after HgCl2 treatment, though it is possible that fibrosis occurs after a longer period of time (supplemental data).


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)

Cyclin D1 and c-myc levels are higher in KO Kidneysa) Western blot analysis and b, c) quantitation of band density for protein levels of cyclin D1, c-myc and β-catenin. Fig 6d & 6c based on two time course studies**, P<0.001. ***, P<0.0001. Data= mean ± SD
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3472082&req=5

Figure 6: Cyclin D1 and c-myc levels are higher in KO Kidneysa) Western blot analysis and b, c) quantitation of band density for protein levels of cyclin D1, c-myc and β-catenin. Fig 6d & 6c based on two time course studies**, P<0.001. ***, P<0.0001. Data= mean ± SD
Mentions: To examine the mechanism for the higher rate of proliferation in the KO mice, protein levels of the pro-proliferative factors, cyclin D1, c-myc and β-catenin, known to be regulated by GSK3β were measured. Cyclin D1 and c-myc levels in the kidney cortex were markedly upregulated in KO mice compared to WT mice, especially on days 1–4 (Fig 6a). Interestingly, cyclin D1 levels decreased by day 6 in the KO mice, while in the WT mice, the highest cyclin D1 levels were observed on days 6 and 8 (Fig 6b). c-myc levels were significantly higher in KO mice on day 3, 4 and 6 compared to that in WT mice (Fig 6c). β-catenin levels did not differ significantly between the WT and KO groups. These results indicated an accelerated rate of proliferation in KO mice when compared to WT mice. Examination of renal fibrosis by sirius red staining, a marker of collagen, revealed no significant difference between the WT and KO mice 8 days after HgCl2 treatment, though it is possible that fibrosis occurs after a longer period of time (supplemental data).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus