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Nox-4 deletion reduces oxidative stress and injury by PKC-α-associated mechanisms in diabetic nephropathy.

Thallas-Bonke V, Jha JC, Gray SP, Barit D, Haller H, Schmidt HH, Coughlan MT, Cooper ME, Forbes JM, Jandeleit-Dahm KA - Physiol Rep (2014)

Bottom Line: Nox4 deletion attenuated diabetes-associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation.Lack of Nox4 resulted in a decrease in diabetes-induced renal cortical ROS derived from the mitochondria and the cytosol, urinary isoprostanes, and PKC activity.Downregulation of the PKC pathway was observed in tandem with reduced expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1 and restoration of the podocyte slit pore protein nephrin.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Melbourne, Victoria, Australia Department of Medicine, Austin and Northern Clinical Schools, University of Melbourne, Melbourne, Victoria, Australia.

No MeSH data available.


Related in: MedlinePlus

Renal parameters at 20 weeks. A) Urinary VEGF excretion. B) Computer‐aided analysis of immunohistochemical staining of glomerular nephrin expression, C) Representative photomicrographs of nephrin immunohistochemical staining of renal cortex, (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.01 versus WT‐C; †P <0.05 versus WT‐D; ‡P <0.001 versus WT‐C; §P <0.01 versus WT‐D, n =8–10/group; all scale bars 50 μm.
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fig03: Renal parameters at 20 weeks. A) Urinary VEGF excretion. B) Computer‐aided analysis of immunohistochemical staining of glomerular nephrin expression, C) Representative photomicrographs of nephrin immunohistochemical staining of renal cortex, (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.01 versus WT‐C; †P <0.05 versus WT‐D; ‡P <0.001 versus WT‐C; §P <0.01 versus WT‐D, n =8–10/group; all scale bars 50 μm.

Mentions: The diabetes‐induced increase in albuminuria in wild‐type diabetic (WT‐D) mice was ameliorated in the Nox4−/− diabetic mice (KO‐D) (Fig. 2A). Plasma cystatin C, regarded as a more sensitive marker of glomerular filtration rate than serum creatinine (Dharnidharka et al. 2002), was decreased in both WT and Nox4−/− diabetic mice (Fig. 2B) indicating that hyperfiltration was not normalized by Nox4 deletion. Albuminuria has been previously linked to VEGF expression including diabetes (Sung et al. 2006; Ziyadeh and Wolf 2008). Indeed, there was an increase in urinary VEGF in WT diabetic mice (Fig. 3A), which was normalized in Nox4−/− mice. There was a concomitant decrease in the expression of glomerular nephrin in the diabetic mice, which was also abrogated in the Nox4 KO‐D mice (Fig. 3B and C).


Nox-4 deletion reduces oxidative stress and injury by PKC-α-associated mechanisms in diabetic nephropathy.

Thallas-Bonke V, Jha JC, Gray SP, Barit D, Haller H, Schmidt HH, Coughlan MT, Cooper ME, Forbes JM, Jandeleit-Dahm KA - Physiol Rep (2014)

Renal parameters at 20 weeks. A) Urinary VEGF excretion. B) Computer‐aided analysis of immunohistochemical staining of glomerular nephrin expression, C) Representative photomicrographs of nephrin immunohistochemical staining of renal cortex, (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.01 versus WT‐C; †P <0.05 versus WT‐D; ‡P <0.001 versus WT‐C; §P <0.01 versus WT‐D, n =8–10/group; all scale bars 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4255803&req=5

fig03: Renal parameters at 20 weeks. A) Urinary VEGF excretion. B) Computer‐aided analysis of immunohistochemical staining of glomerular nephrin expression, C) Representative photomicrographs of nephrin immunohistochemical staining of renal cortex, (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.01 versus WT‐C; †P <0.05 versus WT‐D; ‡P <0.001 versus WT‐C; §P <0.01 versus WT‐D, n =8–10/group; all scale bars 50 μm.
Mentions: The diabetes‐induced increase in albuminuria in wild‐type diabetic (WT‐D) mice was ameliorated in the Nox4−/− diabetic mice (KO‐D) (Fig. 2A). Plasma cystatin C, regarded as a more sensitive marker of glomerular filtration rate than serum creatinine (Dharnidharka et al. 2002), was decreased in both WT and Nox4−/− diabetic mice (Fig. 2B) indicating that hyperfiltration was not normalized by Nox4 deletion. Albuminuria has been previously linked to VEGF expression including diabetes (Sung et al. 2006; Ziyadeh and Wolf 2008). Indeed, there was an increase in urinary VEGF in WT diabetic mice (Fig. 3A), which was normalized in Nox4−/− mice. There was a concomitant decrease in the expression of glomerular nephrin in the diabetic mice, which was also abrogated in the Nox4 KO‐D mice (Fig. 3B and C).

Bottom Line: Nox4 deletion attenuated diabetes-associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation.Lack of Nox4 resulted in a decrease in diabetes-induced renal cortical ROS derived from the mitochondria and the cytosol, urinary isoprostanes, and PKC activity.Downregulation of the PKC pathway was observed in tandem with reduced expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1 and restoration of the podocyte slit pore protein nephrin.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Complications Division, Baker IDI Heart & Diabetes Institute, JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Melbourne, Victoria, Australia Department of Medicine, Austin and Northern Clinical Schools, University of Melbourne, Melbourne, Victoria, Australia.

No MeSH data available.


Related in: MedlinePlus