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: Taketoshi Kushiyama, Takashi Oda, Kojiro Yamamoto, Keishi Higashi, Atsushi Watanabe, Hanako Takechi, Takahiro Uchida, Naoki Oshima, Yutaka Sakurai, Soichiro Miura, Hiroo Kumagai
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 304 Issue 11 Pg. F1325-34 (Jun 01 2013) ISSN: 1522-1466 [Electronic] United States
• PMID: 23552860 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Actins
• Angiotensin II Type 1 Receptor Blockers
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 antigen, human
• Enzyme Inhibitors
• Imidazoles
• Lectins, C-Type
• Mannose Receptor
• Mannose-Binding Lectins
• Membrane Proteins
• RNA, Messenger
• Receptors, Cell Surface
• Tetrazoles
• nephrin
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• olmesartan
• rho-Associated Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (administration & dosage, analogs & derivatives)
• Actins (analysis)
• Angiotensin II Type 1 Receptor Blockers (therapeutic use)
• Animals
• Antigens, CD (genetics)
• Antigens, Differentiation, Myelomonocytic (genetics)
• Enzyme Inhibitors (administration & dosage)
• Hypercholesterolemia (complications)
• Imidazoles (therapeutic use)
• Kidney Glomerulus (chemistry)
• Lectins, C-Type (genetics)
• Macrophages (chemistry, classification)
• Male
• Mannose Receptor
• Mannose-Binding Lectins (genetics)
• Membrane Proteins (analysis)
• Microscopy, Electron
• Phenotype
• Proteinuria (drug therapy)
• RNA, Messenger (analysis)
• Rats
• Receptors, Cell Surface (genetics)
• Renal Insufficiency, Chronic (drug therapy, etiology)
• Tetrazoles (therapeutic use)
• rho-Associated Kinases (antagonists & inhibitors)