Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction

Kidney Int. 2002 May;61(5):1684-95. doi: 10.1046/j.1523-1755.2002.00328.x.

Abstract

Background: The small GTPase Rho is involved in cell-to-substratum adhesion and cell contraction. These actions of Rho mediated by downstream Rho effectors such as Rho-associated coiled-coil forming protein kinase (ROCK) may be partly responsible for the progression of renal interstitial fibrosis.

Methods: The anti-fibrosis effects of Y-27632, a specific ROCK inhibitor, were studied both in vivo (unilateral ureteral obstruction; UUO) and in vitro. To investigate the therapeutic efficacy of Y-27632 in UUO kidneys, smooth muscle alpha actin (SMalphaA) expression, macrophage infiltration and fibrosis in the obstructed kidneys were studied. SMalphaA, transforming growth factor beta (TGF-beta), alpha1 (I) collagen, osteopontin, macrophage chemoattractant peptide-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) gene expression were examined by Northern blotting. To elucidate the mechanism linking the Rho-ROCK pathway with renal fibrosis, the effects of Y-27632 on in vitro cell proliferation and cell migration were studied.

Results: In vivo analysis showed that Y-27632 suppressed SMalphaA expression, macrophage infiltration and interstitial fibrosis, and that Y-27632 suppressed SMalphaA, TGF-beta and alpha1 (I) collagen mRNA expression. In vitro analysis showed that Y-27632 did not suppress proliferation of renal fibroblasts but suppressed migration of macrophages.

Conclusions: The Rho-ROCK system may play an important role in the development of tissue fibrosis, and the Rho-ROCK signaling pathway may be a new therapeutic target for preventing interstitial fibrosis in progressive renal disease.

MeSH terms

  • Actins / genetics
  • Administration, Oral
  • Amides / pharmacology*
  • Animals
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Fibrosis
  • Gene Expression / drug effects
  • Intracellular Signaling Peptides and Proteins
  • Kidney / pathology*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Mice
  • Nephritis, Interstitial / drug therapy*
  • Nephritis, Interstitial / pathology
  • Nephritis, Interstitial / prevention & control
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Pyridines / pharmacology*
  • RNA, Messenger / analysis
  • Signal Transduction / drug effects
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / pathology*
  • ras Proteins
  • rho GTP-Binding Proteins / genetics
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / genetics
  • rhoB GTP-Binding Protein / genetics
  • rhoC GTP-Binding Protein

Substances

  • Actins
  • Amides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Pyridines
  • RNA, Messenger
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Rhoc protein, mouse
  • ras Proteins
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoB GTP-Binding Protein
  • rhoC GTP-Binding Protein