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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

HgCl2 induced apoptosis is reduced in KO micea) TUNEL nuclear staining in renal cortex, 24h after HgCl2 treatment and b) quantitation which shows reduced TUNEL positive nuclei in KO group. c) Cleaved caspase 3 and activated Bax levels are lower by Western blot in KO kidney compared to WT (d & e). **, P<0.001, ***, P<0.0001. Fig 4d & e based on two time-course studies. Fig 4b n=5 per group.
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Figure 4: HgCl2 induced apoptosis is reduced in KO micea) TUNEL nuclear staining in renal cortex, 24h after HgCl2 treatment and b) quantitation which shows reduced TUNEL positive nuclei in KO group. c) Cleaved caspase 3 and activated Bax levels are lower by Western blot in KO kidney compared to WT (d & e). **, P<0.001, ***, P<0.0001. Fig 4d & e based on two time-course studies. Fig 4b n=5 per group.

Mentions: To examine if the reduced levels of injury in the KO mice could be attributed to a decreased rate of apoptosis, TUNEL assay was carried out. Within 24h after HgCl2 treatment, 12% of nuclei were TUNEL positive in the WT kidney compared to only 4% in KO (Fig 4a, 4b). These apoptotic cells were mostly in proximal tubules as shown by an immunoperoxidase- labeled TUNEL assay (Supplemental Fig. 1). This result indicated that apoptosis was associated with tissue injury early in HgCl2-induced AKI and the rate of apoptosis was reduced in KO mice.


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)

HgCl2 induced apoptosis is reduced in KO micea) TUNEL nuclear staining in renal cortex, 24h after HgCl2 treatment and b) quantitation which shows reduced TUNEL positive nuclei in KO group. c) Cleaved caspase 3 and activated Bax levels are lower by Western blot in KO kidney compared to WT (d & e). **, P<0.001, ***, P<0.0001. Fig 4d & e based on two time-course studies. Fig 4b n=5 per group.
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Related In: Results  -  Collection

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

Figure 4: HgCl2 induced apoptosis is reduced in KO micea) TUNEL nuclear staining in renal cortex, 24h after HgCl2 treatment and b) quantitation which shows reduced TUNEL positive nuclei in KO group. c) Cleaved caspase 3 and activated Bax levels are lower by Western blot in KO kidney compared to WT (d & e). **, P<0.001, ***, P<0.0001. Fig 4d & e based on two time-course studies. Fig 4b n=5 per group.
Mentions: To examine if the reduced levels of injury in the KO mice could be attributed to a decreased rate of apoptosis, TUNEL assay was carried out. Within 24h after HgCl2 treatment, 12% of nuclei were TUNEL positive in the WT kidney compared to only 4% in KO (Fig 4a, 4b). These apoptotic cells were mostly in proximal tubules as shown by an immunoperoxidase- labeled TUNEL assay (Supplemental Fig. 1). This result indicated that apoptosis was associated with tissue injury early in HgCl2-induced AKI and the rate of apoptosis was reduced in KO mice.

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