Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice.

Abstract

Diabetes induces the activation of several protein kinase C (PKC) isoforms in the renal glomeruli. We used PKC-beta(-/-) mice to examine the action of PKC-beta isoforms in diabetes-induced oxidative stress and renal injury at 8 and 24 weeks of disease. Diabetes increased PKC activity in renal cortex of wild-type mice and was significantly reduced (<50% of wild-type) in diabetic PKC-beta(-/-) mice. In wild-type mice, diabetes increased the translocation of PKC-alpha and -beta1 to the membrane, whereas only PKC-alpha was elevated in PKC-beta(-/-) mice. Increases in urinary isoprostane and 8-hydroxydeoxyguanosine, parameters of oxidative stress, in diabetic PKC-beta(-/-) mice were significantly reduced compared with diabetic wild-type mice. Diabetes increased NADPH oxidase activity and the expressions of p47(phox), Nox2, and Nox4 mRNA levels in the renal cortex and were unchanged in diabetic PKC-beta(-/-) mice. Increased expression of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), and collagens IV and VI found in diabetic wild-type mice was attenuated in diabetic PKC-beta(-/-) mice. Diabetic PKC-beta(-/-) mice were protected from renal hypertrophy, glomerular enlargement, and hyperfiltration observed in diabetic wild-type mice and had less proteinuria. Lack of PKC-beta can protect against diabetes-induced renal dysfunction, fibrosis, and increased expressions of Nox2 and -4, ET-1, VEGF, TGF-beta, CTGF, and oxidant production.

• Authors: Yuzuru Ohshiro, Ronald C Ma, Yutaka Yasuda, Junko Hiraoka-Yamamoto, Allen C Clermont, Keiji Isshiki, Kunimasa Yagi, Emi Arikawa, Timothy S Kern, George L King
• Journal: Diabetes (Diabetes) Vol. 55 Issue 11 Pg. 3112-20 (Nov 2006) ISSN: 0012-1797 [Print] United States
• PMID: 17065350 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cytokines
• Protein Kinase C
• Protein Kinase C beta

Topics

• Animals
• Blood Glucose (metabolism)
• Blood Pressure
• Body Weight
• Cytokines (genetics)
• Diabetes Mellitus, Experimental (genetics, physiopathology)
• Diabetic Nephropathies (prevention & control)
• Enzyme Activation
• Fibrosis (prevention & control)
• Gene Expression Regulation
• Glomerular Filtration Rate
• Kidney Cortex (enzymology, physiology, physiopathology)
• Mice
• Mice, Knockout
• Oxidative Stress (physiology)
• Polymerase Chain Reaction
• Protein Kinase C (deficiency, genetics, metabolism)
• Protein Kinase C beta
• Reference Values