A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats.
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.
Kikuchi
Yuichi
Y
Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. grd1615@ndmc.ac.jp
Yamada
Muneharu
M
Imakiire
Toshihiko
T
Kushiyama
Taketoshi
T
Higashi
Keishi
K
Hyodo
Naomi
N
Yamamoto
Kojiro
K
Oda
Takashi
T
Suzuki
Shigenobu
S
Miura
Soichiro
S
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D050356:Lipid Metabolism; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D020334:Rats, Inbred OLETF; D012234:Rho Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D054460:rho-Associated Kinases
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001786:Blood Glucose; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D012234:Rho Factor; D013777:Tetrazoles; D054460:rho-Associated Kinases; C437965:olmesartan; C499850:Ppp1r12a protein, rat; C049347:fasudil