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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

KO mice show higher survival rate following HgCl2 treatmentKaplan-Meier survival curve of WT and KO mice injected with a single subcutaneous injection of 8.14 mg/kg body weight of HgCl2. *, P<0.01, n=20 per group
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Figure 2: KO mice show higher survival rate following HgCl2 treatmentKaplan-Meier survival curve of WT and KO mice injected with a single subcutaneous injection of 8.14 mg/kg body weight of HgCl2. *, P<0.01, n=20 per group

Mentions: When treated with 8.14 mg/kg body weight of HgCl2, a 10% mortality rate was observed in both WT and KO groups within 24 hours (Fig 2). By days 2–3, the mortality rate further increased to 40% in the WT group, while it remained unchanged in the KO cohort, indicating that GSK3β gene deletion in the proximal tubule reduced HgCl2-induced mortality (Fig 2). Kidneys showed tubular dilatation, cellular necrosis and loss of brush border in both WT and KO mice by day 2 after HgCl2 treatment (Fig 3a). Semiquantitative injury score showed that on day 2, injury score in the KO mice was only half of that in WT mice (Fig 3b). The injury score did not change significantly in WT mice by day 4 and remained 16-fold higher than baseline values on day 6. In the KO mice, the injury score decreased by 1.8-fold on day 4 and attained baseline levels by day 6. Blood urea nitrogen (BUN) levels increased by 7.8-fold in WT and 3.5-fold in the KO group by day 2 after HgCl2 treatment, compared to baseline (20±6 vs 155±15 mg/dl in WT and 25±7 vs 87±18 mg/dl in KO). By days 4 and 6, BUN levels in the KO mice were reduced by 42% and 60%, respectively, returning to close to baseline levels. In contrast, BUN levels remained essentially unchanged in the WT group on day 4, followed by a 40% decrease on day 6 but failed to reach baseline levels even by day 8 (Fig 3c). Plasma creatinine levels showed a similar pattern (Fig 3d).


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)

KO mice show higher survival rate following HgCl2 treatmentKaplan-Meier survival curve of WT and KO mice injected with a single subcutaneous injection of 8.14 mg/kg body weight of HgCl2. *, P<0.01, n=20 per group
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: KO mice show higher survival rate following HgCl2 treatmentKaplan-Meier survival curve of WT and KO mice injected with a single subcutaneous injection of 8.14 mg/kg body weight of HgCl2. *, P<0.01, n=20 per group
Mentions: When treated with 8.14 mg/kg body weight of HgCl2, a 10% mortality rate was observed in both WT and KO groups within 24 hours (Fig 2). By days 2–3, the mortality rate further increased to 40% in the WT group, while it remained unchanged in the KO cohort, indicating that GSK3β gene deletion in the proximal tubule reduced HgCl2-induced mortality (Fig 2). Kidneys showed tubular dilatation, cellular necrosis and loss of brush border in both WT and KO mice by day 2 after HgCl2 treatment (Fig 3a). Semiquantitative injury score showed that on day 2, injury score in the KO mice was only half of that in WT mice (Fig 3b). The injury score did not change significantly in WT mice by day 4 and remained 16-fold higher than baseline values on day 6. In the KO mice, the injury score decreased by 1.8-fold on day 4 and attained baseline levels by day 6. Blood urea nitrogen (BUN) levels increased by 7.8-fold in WT and 3.5-fold in the KO group by day 2 after HgCl2 treatment, compared to baseline (20±6 vs 155±15 mg/dl in WT and 25±7 vs 87±18 mg/dl in KO). By days 4 and 6, BUN levels in the KO mice were reduced by 42% and 60%, respectively, returning to close to baseline levels. In contrast, BUN levels remained essentially unchanged in the WT group on day 4, followed by a 40% decrease on day 6 but failed to reach baseline levels even by day 8 (Fig 3c). Plasma creatinine levels showed a similar pattern (Fig 3d).

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