title: Protective effects of Rho kinase inhibitor fasudil on rats with chronic kidney disease.
abstract: The protective effects of Rho kinase inhibitor fasudil against renal diseases have recently been reported. We compared the therapeutic effects of fasudil on the spontaneously hypercholesterolemic (SHC) rat, a model of chronic kidney disease (CKD) with proteinuria, with those of the angiotensin receptor blocker olmesartan (OL) by paying attention to the proteinuria and the macrophage phenotype. SHC rats were allocated to six treatment groups: a vehicle (Ve) group, a low-dose fasudil (FL) group, a high-dose fasudil (FH) group, an OL group, a combination of low-dose fasudil and OL (CL) group, and a combination of high-dose fasudil and OL (CH) group. Sprague-Dawley rats treated with vehicle served as a control (n = 7/each). The rats were treated for 24 wk. Compared with the Ve group, proteinuria was significantly decreased in the FH, OL, and CL groups, and it completely disappeared in the CH group. Glomerular stainings of nephrin and F-actin were focally impaired in the Ve group but were restored in the CH group. Western blotting showed that the CH group had significantly increased renal nephrin expression compared with the Ve group. Interstitial infiltration of macrophages was significantly increased in the Ve group, which was significantly attenuated in all treatment groups. The ratio of CD206 (M2 macrophage marker) to CD68 mRNA was significantly greater in the CH group than in the Ve group. These results indicate that fasudil with OL reduces proteinuria by protecting podocyte integrity and alters the interstitial macrophage density/phenotype, thereby exerting renoprotective effects against CKD.
authors.affiliation: Department of Nephrology, National Defense Medical College, Saitama, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Kushiyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Oda
authors.forename: Kojiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Keishi
authors.initials: K
authors.lastname: Higashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Hanako
authors.initials: H
authors.lastname: Takechi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uchida
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Soichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000199:Actins / Q000032:analysis; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000150:complications; D007093:Imidazoles / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000737:chemistry; D037181:Lectins, C-Type / Q000235:genetics; D008264:Macrophages / Q000737:chemistry / Q000145:classification; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis; D008854:Microscopy, Electron; D010641:Phenotype; D011507:Proteinuria / Q000188:drug therapy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology; D013777:Tetrazoles / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D000097382:CD68 Molecule
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004791:Enzyme Inhibitors; D007093:Imidazoles; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D013777:Tetrazoles; D054460:rho-Associated Kinases; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C113267:nephrin; C437965:olmesartan; C049347:fasudil
keywords: Rho kinase inhibitor; angiotensin receptor blocker; chronic kidney disease; macrophage; podocyte