Document Detail


A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats.
MedLine Citation:
PMID:  17332527     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fasudil, a Rho-kinase inhibitor, may improve insulin signaling. However, its long-term effect on metabolic abnormalities and its preventive effect on diabetic nephropathy are still unknown. We assessed these effects of fasudil in insulin-resistant diabetic rats, comparing them with those of an angiotensin II receptor blocker, olmesartan. Male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka, non-diabetic control, rats at 15 weeks of age were used. OLETF rats were randomized to receive a low or a high dose of fasudil or olmesartan for 25 weeks. To examine the therapeutic effects after the development of diabetes, OLETF rats at 30 weeks of age were given fasudil for 10 weeks. Administration of high-dose fasudil completely suppressed the development of diabetes, obesity, and dyslipidemia and increased serum adiponectin levels in OLETF rats. High-dose olmesartan also decreased hemoglobin A1c and increased serum adiponectin. There was a significant correlation between hemoglobin A1c and serum adiponectin or free fatty acid levels. The treatment with high-dose fasudil ameliorated proteinuria, glomerulosclerosis, renal interstitial fibrosis, and macrophage infiltration in OLETF rats. Olmesartan, even at the low dose, suppressed renal complications. The treatment with fasudil after the development of diabetes improved the metabolic abnormalities in OLETF rats, but could not suppress the progression of nephropathy. We conclude that the long-term treatment with fasudil prevents the development of diabetes, at least in part, by improving adipocyte differentiation in insulin-resistant diabetic rats. Early use of fasudil may prevent diabetic nephropathy.
Authors:
Yuichi Kikuchi; Muneharu Yamada; Toshihiko Imakiire; Taketoshi Kushiyama; Keishi Higashi; Naomi Hyodo; Kojiro Yamamoto; Takashi Oda; Shigenobu Suzuki; Soichiro Miura
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of endocrinology     Volume:  192     ISSN:  0022-0795     ISO Abbreviation:  J. Endocrinol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-02     Completed Date:  2007-04-30     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0375363     Medline TA:  J Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  595-603     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. grd1615@ndmc.ac.jp
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MeSH Terms
Descriptor/Qualifier:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*,  therapeutic use
Animals
Blood Glucose / metabolism
Carrier Proteins / metabolism
Diabetes Mellitus, Type 1 / metabolism,  pathology,  prevention & control*
Diabetic Nephropathies / metabolism,  pathology,  prevention & control
Enzyme Inhibitors / therapeutic use
Hemoglobin A, Glycosylated / metabolism
Imidazoles / pharmacology
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Kidney / chemistry,  pathology
Lipid Metabolism
Male
Phosphoprotein Phosphatases / metabolism
Protein Phosphatase 1
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Rats
Rats, Inbred OLETF
Rho Factor / metabolism
Signal Transduction / physiology
Tetrazoles / pharmacology
rho-Associated Kinases
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Carrier Proteins; 0/Enzyme Inhibitors; 0/Hemoglobin A, Glycosylated; 0/Imidazoles; 0/Intracellular Signaling Peptides and Proteins; 0/Rho Factor; 0/Tetrazoles; 0/olmesartan; 103745-39-7/fasudil; 84477-87-2/1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/rho-Associated Kinases; EC 3.1.3.16/Phosphoprotein Phosphatases; EC 3.1.3.16/Ppp1r12a protein, rat; EC 3.1.3.16/Protein Phosphatase 1

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