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Targeting of Rho kinase ameliorates impairment of diabetic endothelial function in intrarenal artery.

Yin H, Ru H, Yu L, Kang Y, Lin G, Liu C, Sun L, Shi L, Sun Q, Liu C - Int J Mol Sci (2013)

Bottom Line: Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney.Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor.In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Center for Medical Science, Hangzhou Normal University, Hangzhou 310036, China. liucuiqing@hznu.edu.cn.

ABSTRACT
Endothelial dysfunction in kidney vasculature is the initial and key element for nephropathy in diabetes mellitus. Accumulating evidence suggests the protective role of Rho kinase inhibitors in endothelial dysfunction via modulating eNOS activity and NO production. However, the role of Rho kinase in diabetes-related endothelial dysfunction in kidney vasculature and the relevant mechanisms remain unknown. We assessed whether pharmacological inhibition of Rho kinase attenuates endothelial dysfunction in intrarenal arteries from type 1 diabetic rats. Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney. Fasudil treatment showed no improvement in diabetes-related abnormality in metabolic indices, but it significantly ameliorated endothelial dysfunction in intrarenal arteries and lessened the mesangial matrix expansion in the kidney cortex. Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor. In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.

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Effects of Rho kinase inhibition on metabolic parameters in diabetic rats. (A) Body weight of rats after 4-week treatment with fasudil; (B) Blood glucose of rats after 4-week treatment with fasudil; (C–E) Total cholesterol level (C), triglyceride level (D) and creatinine level (E) in plasma of rats after 4-week treatment with fasudil; (F) Blood pressure of rats during 4-week treatment with fasudil; (G,H) kidney weight, kidney weight/body weight ratio (G) and liver weight, liver weight/body weight ratio (H) of rats after 4-week treatment with fasudil. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control group. Data are mean ± S.E.M. from five to six different rats.
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f1-ijms-14-20282: Effects of Rho kinase inhibition on metabolic parameters in diabetic rats. (A) Body weight of rats after 4-week treatment with fasudil; (B) Blood glucose of rats after 4-week treatment with fasudil; (C–E) Total cholesterol level (C), triglyceride level (D) and creatinine level (E) in plasma of rats after 4-week treatment with fasudil; (F) Blood pressure of rats during 4-week treatment with fasudil; (G,H) kidney weight, kidney weight/body weight ratio (G) and liver weight, liver weight/body weight ratio (H) of rats after 4-week treatment with fasudil. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control group. Data are mean ± S.E.M. from five to six different rats.

Mentions: There were no differences in body weight or blood glucose between the groups at baseline (data not shown). Diabetic rats demonstrated reduced weight gain and hyperglycemia (Figure 1A,B), indicating a successful induction of diabetic model. Total cholesterol was significantly increased following STZ injection while there were no differences in plasma triglyceride or creatinine between the two groups, although there was a trend towards increment in tryglyceride in STZ-treated rats (Figure 1C–E). There is a vast literature showing an increase in relative kidney size in diabetic nephropathy in humans and rodent diabetic models. Consistent with it, STZ injection resulted in renal hypertrophy (as assessed by kidney weight/body weight) at the end of the treatment period, although no difference was observed by comparing organ weight itself between groups (Figure 1G). Similar results were noticed with liver (Figure 1H). However, treatment with Rho kinase inhibitor, fasudil, had no effects on these general characteristics (Figure 1), which was in agreement with the study by Komers et al. [18].


Targeting of Rho kinase ameliorates impairment of diabetic endothelial function in intrarenal artery.

Yin H, Ru H, Yu L, Kang Y, Lin G, Liu C, Sun L, Shi L, Sun Q, Liu C - Int J Mol Sci (2013)

Effects of Rho kinase inhibition on metabolic parameters in diabetic rats. (A) Body weight of rats after 4-week treatment with fasudil; (B) Blood glucose of rats after 4-week treatment with fasudil; (C–E) Total cholesterol level (C), triglyceride level (D) and creatinine level (E) in plasma of rats after 4-week treatment with fasudil; (F) Blood pressure of rats during 4-week treatment with fasudil; (G,H) kidney weight, kidney weight/body weight ratio (G) and liver weight, liver weight/body weight ratio (H) of rats after 4-week treatment with fasudil. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control group. Data are mean ± S.E.M. from five to six different rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821615&req=5

f1-ijms-14-20282: Effects of Rho kinase inhibition on metabolic parameters in diabetic rats. (A) Body weight of rats after 4-week treatment with fasudil; (B) Blood glucose of rats after 4-week treatment with fasudil; (C–E) Total cholesterol level (C), triglyceride level (D) and creatinine level (E) in plasma of rats after 4-week treatment with fasudil; (F) Blood pressure of rats during 4-week treatment with fasudil; (G,H) kidney weight, kidney weight/body weight ratio (G) and liver weight, liver weight/body weight ratio (H) of rats after 4-week treatment with fasudil. *p < 0.05, **p < 0.01, ***p < 0.001 compared with control group. Data are mean ± S.E.M. from five to six different rats.
Mentions: There were no differences in body weight or blood glucose between the groups at baseline (data not shown). Diabetic rats demonstrated reduced weight gain and hyperglycemia (Figure 1A,B), indicating a successful induction of diabetic model. Total cholesterol was significantly increased following STZ injection while there were no differences in plasma triglyceride or creatinine between the two groups, although there was a trend towards increment in tryglyceride in STZ-treated rats (Figure 1C–E). There is a vast literature showing an increase in relative kidney size in diabetic nephropathy in humans and rodent diabetic models. Consistent with it, STZ injection resulted in renal hypertrophy (as assessed by kidney weight/body weight) at the end of the treatment period, although no difference was observed by comparing organ weight itself between groups (Figure 1G). Similar results were noticed with liver (Figure 1H). However, treatment with Rho kinase inhibitor, fasudil, had no effects on these general characteristics (Figure 1), which was in agreement with the study by Komers et al. [18].

Bottom Line: Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney.Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor.In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Center for Medical Science, Hangzhou Normal University, Hangzhou 310036, China. liucuiqing@hznu.edu.cn.

ABSTRACT
Endothelial dysfunction in kidney vasculature is the initial and key element for nephropathy in diabetes mellitus. Accumulating evidence suggests the protective role of Rho kinase inhibitors in endothelial dysfunction via modulating eNOS activity and NO production. However, the role of Rho kinase in diabetes-related endothelial dysfunction in kidney vasculature and the relevant mechanisms remain unknown. We assessed whether pharmacological inhibition of Rho kinase attenuates endothelial dysfunction in intrarenal arteries from type 1 diabetic rats. Fasudil, a Rho kinase inhibitor effectively decreased the phosphorylated level of MYPT1 without affecting the expression of ROCKs in the kidney. Fasudil treatment showed no improvement in diabetes-related abnormality in metabolic indices, but it significantly ameliorated endothelial dysfunction in intrarenal arteries and lessened the mesangial matrix expansion in the kidney cortex. Mechanistically, superoxide production in the intrarenal artery and NOX4 member of NADPH oxidase in the renal cortex that contribute to diabetic nephropathy were also prevented by the Rho kinase inhibitor. In conclusion, the present results indicate that Rho kinase is involved in endothelial dysfunction in type 1 diabetes via enhancement of oxidative stress and provides new evidence for Rho kinase inhibitors as potential therapeutic agents for the treatment of diabetic nephropathy.

Show MeSH
Related in: MedlinePlus