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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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Related in: MedlinePlus

Renal GSK3β activity changes in response to HgCl2 treatmentWestern blot analysis of tissue lysates from whole renal cortex of WT mice injected once with 8.14mg/kg of HgCl2. a) Inactive phosphorylated GSK3β levels initially decreased within 6 hours after HgCl2 treatment and b) increased to above baseline by 24h. β-Catenin levels also increased on days 2–5.
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Figure 9: Renal GSK3β activity changes in response to HgCl2 treatmentWestern blot analysis of tissue lysates from whole renal cortex of WT mice injected once with 8.14mg/kg of HgCl2. a) Inactive phosphorylated GSK3β levels initially decreased within 6 hours after HgCl2 treatment and b) increased to above baseline by 24h. β-Catenin levels also increased on days 2–5.

Mentions: We next examined whether GSK3β activity was regulated in HgCl2-induced AKI. Protein levels of pGSK3β, the inhibited form of GSK3β phosphorylated at Serine 9, decreased to undetectable levels 6h after HgCl2 injection, gradually increasing by 16h (Fig 9a). By 32h, pGSK3β levels increased above baseline levels and remained high for 5 days. Protein levels of β-catenin, a negatively regulated substrate of GSK3 also increased by 48h, consistent with the GSK3 inhibition. These data indicated that, following HgCl2 treatment, GSK3β (and likely also GSK3α) was initially activated and then, subsequently inhibited.


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)

Renal GSK3β activity changes in response to HgCl2 treatmentWestern blot analysis of tissue lysates from whole renal cortex of WT mice injected once with 8.14mg/kg of HgCl2. a) Inactive phosphorylated GSK3β levels initially decreased within 6 hours after HgCl2 treatment and b) increased to above baseline by 24h. β-Catenin levels also increased on days 2–5.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 9: Renal GSK3β activity changes in response to HgCl2 treatmentWestern blot analysis of tissue lysates from whole renal cortex of WT mice injected once with 8.14mg/kg of HgCl2. a) Inactive phosphorylated GSK3β levels initially decreased within 6 hours after HgCl2 treatment and b) increased to above baseline by 24h. β-Catenin levels also increased on days 2–5.
Mentions: We next examined whether GSK3β activity was regulated in HgCl2-induced AKI. Protein levels of pGSK3β, the inhibited form of GSK3β phosphorylated at Serine 9, decreased to undetectable levels 6h after HgCl2 injection, gradually increasing by 16h (Fig 9a). By 32h, pGSK3β levels increased above baseline levels and remained high for 5 days. Protein levels of β-catenin, a negatively regulated substrate of GSK3 also increased by 48h, consistent with the GSK3 inhibition. These data indicated that, following HgCl2 treatment, GSK3β (and likely also GSK3α) was initially activated and then, subsequently inhibited.

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