Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice.
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.
Ohshiro
Yuzuru
Y
Research Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. george.king@joslin.harvard.edu
Ma
Ronald C
RC
Yasuda
Yutaka
Y
Hiraoka-Yamamoto
Junko
J
Clermont
Allen C
AC
Isshiki
Keiji
K
Yagi
Kunimasa
K
Arikawa
Emi
E
Kern
Timothy S
TS
King
George L
GL
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D016207:Cytokines / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control; D004789:Enzyme Activation; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D007672:Kidney Cortex / Q000201:enzymology / Q000502:physiology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D012016:Reference Values
D001786:Blood Glucose; D016207:Cytokines; D011493:Protein Kinase C; D064546:Protein Kinase C beta