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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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Proliferation is accelerated in KO kidneysImmunohistochemical staining and quantitation for a) & b) Ki-67 and c & d) BrdU show more proliferating cells in KO kidneys. **, P<0.001. ***, P<0.0001, n=5 per group, x200 original magnification). immunofluorescence staining for PCNA and LTA shows more dividing cells in proximal tubule cells of KO mice on day 4 after HgCl2 treatment, x400 original magnification.
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Figure 5: Proliferation is accelerated in KO kidneysImmunohistochemical staining and quantitation for a) & b) Ki-67 and c & d) BrdU show more proliferating cells in KO kidneys. **, P<0.001. ***, P<0.0001, n=5 per group, x200 original magnification). immunofluorescence staining for PCNA and LTA shows more dividing cells in proximal tubule cells of KO mice on day 4 after HgCl2 treatment, x400 original magnification.

Mentions: We next determined whether GSK3β gene deletion in proximal tubule cells alters their proliferative response after injury. Ki-67 nuclear staining, a proliferative marker, was higher by 2-fold on day 2 and 3.5-fold on day 4 in the KO group compared to the WT group (500-fold more than baseline) (Fig 5a & 5b). BrdU positive nuclei were also 2.5-fold higher in the KO kidney on day 4 compared to WT (Fig 5c & 5d). Both Ki-67 as well as BrdU staining decreased in KO kidneys after day 4, consistent with the improved renal function and decreased histopathology injury data. Triple immunofluorescence staining of kidneys on day 4 showed that the dividing cells, indicated by PCNA staining, were more abundant in the KO mice, and were primarily located in the proximal tubule (stained with Lotus tetragonolobus agglutinin (LTA)) (Fig 5e).


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)

Proliferation is accelerated in KO kidneysImmunohistochemical staining and quantitation for a) & b) Ki-67 and c & d) BrdU show more proliferating cells in KO kidneys. **, P<0.001. ***, P<0.0001, n=5 per group, x200 original magnification). immunofluorescence staining for PCNA and LTA shows more dividing cells in proximal tubule cells of KO mice on day 4 after HgCl2 treatment, x400 original magnification.
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Related In: Results  -  Collection

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

Figure 5: Proliferation is accelerated in KO kidneysImmunohistochemical staining and quantitation for a) & b) Ki-67 and c & d) BrdU show more proliferating cells in KO kidneys. **, P<0.001. ***, P<0.0001, n=5 per group, x200 original magnification). immunofluorescence staining for PCNA and LTA shows more dividing cells in proximal tubule cells of KO mice on day 4 after HgCl2 treatment, x400 original magnification.
Mentions: We next determined whether GSK3β gene deletion in proximal tubule cells alters their proliferative response after injury. Ki-67 nuclear staining, a proliferative marker, was higher by 2-fold on day 2 and 3.5-fold on day 4 in the KO group compared to the WT group (500-fold more than baseline) (Fig 5a & 5b). BrdU positive nuclei were also 2.5-fold higher in the KO kidney on day 4 compared to WT (Fig 5c & 5d). Both Ki-67 as well as BrdU staining decreased in KO kidneys after day 4, consistent with the improved renal function and decreased histopathology injury data. Triple immunofluorescence staining of kidneys on day 4 showed that the dividing cells, indicated by PCNA staining, were more abundant in the KO mice, and were primarily located in the proximal tubule (stained with Lotus tetragonolobus agglutinin (LTA)) (Fig 5e).

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