The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats.
This study aimed to investigate the effect of the Rho-kinase inhibitor fasudil on the development of diabetic nephropathy and clarify a contribution of the Rho/Rho-kinase pathway to the pathogenesis of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats with an intraperitoneal injection of streptozotocin. Animals were then divided into the following 4 groups; normal control rats, diabetic rats, diabetic rats administered fasudil orally and diabetic rats administered fluvastatin (3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, statin) orally. After 1 month of treatment, neither fasudil nor statin had any influence on blood glucose or blood pressure in diabetic rats. While urinary excretion of albumin and 8-hydroxydeoxyguanosine (8-OHdG) was increased in diabetic rats, both of these increases were abolished by fasudil and statin. Rho activity was enhanced in the renal cortex of diabetic rats compared to normal controls, and this enhancement was abolished by statin treatment. Expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) mRNA was up-regulated in the renal cortex of diabetic rats, and this was abolished by fasudil as well as statin. Expression of NOX4 mRNA (catalytic subunit of NAD(P)H oxidase) was up-regulated in the renal cortex of diabetic rats, an effect which was also abolished by fasudil as well as statin. The present study demonstrates that the Rho/Rho-kinase pathway is involved in up-regulation of TGF-beta, CTGF and NAD(P)H oxidase in diabetic kidney. We conclude that suppression of the Rho/Rho-kinase pathway could be a new strategy for the treatment of diabetic nephropathy.
Gojo
Atsushi
A
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi Minato-ku, Tokyo, 105-8461, Japan.
Utsunomiya
Kazunori
K
Taniguchi
Kanta
K
Yokota
Tamotsu
T
Ishizawa
Shoh
S
Kanazawa
Yasushi
Y
Kurata
Hideaki
H
Tajima
Naoko
N
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D055513:Connective Tissue Growth Factor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D017874:Immediate-Early Proteins / Q000235:genetics; D007211:Indoles / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000235:genetics; D054460:rho-Associated Kinases
D001786:Blood Glucose; C526316:CCN2 protein, rat; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000077340:Fluvastatin; D013311:Streptozocin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002784:Cholesterol; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D003849:Deoxyguanosine; C049347:fasudil