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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 structural data at week 20. A) Glomerulosclerotic index (GSI), B) Representative photomicrographs of PAS stained renal cortex of kidney (×400 magnification), (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.001 versus WT‐C; †P <0.05 versus WT‐C and ‡P <0.05 versus WT‐D, n =8–10/group.
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fig04: Renal structural data at week 20. A) Glomerulosclerotic index (GSI), B) Representative photomicrographs of PAS stained renal cortex of kidney (×400 magnification), (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.001 versus WT‐C; †P <0.05 versus WT‐C and ‡P <0.05 versus WT‐D, n =8–10/group.

Mentions: The GSI, a measure of glomerular damage, was increased with diabetes in the Nox4 WT‐D mice. Nox4 KO‐D mice showed improved GSI compared to WT‐D mice (Fig. 4A and B). Induction of diabetes was associated with an increase in biologically active TGF‐β1 in urine, which was partly, but not fully, reduced in the Nox4 KO‐D mice (Fig. 5A). Further analysis of renal cortical plasma membrane fractions of the diabetic Nox4 deleted mice revealed that the expression of TGF‐β1 activity was normalized compared to the WT‐D mice (Fig. 5B). Consistent with the levels of the prosclerotic cytokine TGF‐β, the protein expression of renal glomerular collagen IV was increased in diabetic WT mice. Furthermore, the Nox4 KO‐D mice had decreased protein expression compared to their WT‐D counterparts. However, Nox4 deleted control mice had significantly lower collagen IV expression when compared to the respective KO‐D mice (Fig. 5C). The extracellular matrix protein fibronectin was also increased in the WT‐D mice and significantly ameliorated with Nox4 deletion (Fig. 5D).


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 structural data at week 20. A) Glomerulosclerotic index (GSI), B) Representative photomicrographs of PAS stained renal cortex of kidney (×400 magnification), (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.001 versus WT‐C; †P <0.05 versus WT‐C and ‡P <0.05 versus WT‐D, n =8–10/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Renal structural data at week 20. A) Glomerulosclerotic index (GSI), B) Representative photomicrographs of PAS stained renal cortex of kidney (×400 magnification), (i) WT‐C; (ii) WT‐D, (iii) Nox4‐KO‐C; (iv) Nox4‐KO‐D, *P <0.001 versus WT‐C; †P <0.05 versus WT‐C and ‡P <0.05 versus WT‐D, n =8–10/group.
Mentions: The GSI, a measure of glomerular damage, was increased with diabetes in the Nox4 WT‐D mice. Nox4 KO‐D mice showed improved GSI compared to WT‐D mice (Fig. 4A and B). Induction of diabetes was associated with an increase in biologically active TGF‐β1 in urine, which was partly, but not fully, reduced in the Nox4 KO‐D mice (Fig. 5A). Further analysis of renal cortical plasma membrane fractions of the diabetic Nox4 deleted mice revealed that the expression of TGF‐β1 activity was normalized compared to the WT‐D mice (Fig. 5B). Consistent with the levels of the prosclerotic cytokine TGF‐β, the protein expression of renal glomerular collagen IV was increased in diabetic WT mice. Furthermore, the Nox4 KO‐D mice had decreased protein expression compared to their WT‐D counterparts. However, Nox4 deleted control mice had significantly lower collagen IV expression when compared to the respective KO‐D mice (Fig. 5C). The extracellular matrix protein fibronectin was also increased in the WT‐D mice and significantly ameliorated with Nox4 deletion (Fig. 5D).

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