Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats.
OBJECTIVE
The present study was designed to clarify whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor.


RESULTS
Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide (ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinasealpha, Rho-kinasebeta, collagen I and collagen III, and transforming growth factor-beta (TGF-beta) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (-25%) and ANP (-49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-beta (-20%), collagen I (-23%), and collagen III (-24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS.


CONCLUSIONS
These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. nishikim@dokkyomed.ac.jp
Toshio
T
Nishikimi
Kazumi
K
Akimoto
Xin
X
Wang
Yosuke
Y
Mori
Kazuyoshi
K
Tadokoro
Yayoi
Y
Ishikawa
Hiroaki
H
Shimokawa
Hidehiko
H
Ono
Hiroaki
H
Matsuoka
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins; D007672:Kidney Cortex / Q000098:blood supply / Q000473:pathology / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics; D020743:rhoB GTP-Binding Protein / Q000235:genetics
D024042:Collagen Type I; D024061:Collagen Type III; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; C049347:fasudil