Targeted Inhibition of Renal Rho Kinase Reduces Macrophage Infiltration and Lymphangiogenesis in Acute Renal Allograft Rejection

Eur J Pharmacol. 2012 Nov 5;694(1-3):111-9. doi: 10.1016/j.ejphar.2012.08.010. Epub 2012 Sep 3.

Abstract

The Rho kinase pathway plays an important role in epithelial dedifferentiation and inflammatory cell infiltration. Recent studies suggest that inflammation promotes lymphangiogenesis, which has been associated with renal allograft rejection. We investigated whether targeted inhibition of the Rho kinase pathway in proximal tubular cells reduces inflammation and lymphangiogenesis in acute renal allograft rejection. The Rho kinase inhibitor Y27632 was coupled to lysozyme (Y27632-lysozyme), providing a kidney-specific conjugate that can release its drug in proximal tubular cells. Isogenic (Fisher-Fisher, n=18), or allogenic (Fisher-Lewis, n=24) kidney transplantations were performed, with the contralateral kidney remaining in situ. To elicit acute rejection, no immunosuppressive treatment was given. Animals were treated daily with Y27632-lysozyme (10 mg/kg/day i.v.) or vehicle (saline i.v.) until sacrifice (1 or 4 days post-transplantation). After allogenic transplantation, interstitial macrophage accumulation was strongly reduced by Y27632-lysozyme at day 4 after transplantation. Interstitial lymphangiogenesis, which was induced in allografts as compared to control kidney, was also reduced by renal Rho kinase inhibition at day 4 after transplantation. The increase of vimentin and procollagen-1alpha1 gene expression in renal allografts from day 1 to day 4 after transplantation was significantly reduced by Y27632-lysozyme. Y27632-lysozyme did not affect systolic blood pressure in isogenic or allogenic transplantation groups. In cultured tubular epithelial cells (NRK-52E), Rho kinase inhibition dose-dependently reduced IL-1β-induced MCP-1 gene expression. Renal inhibition of Rho kinase causes a marked reduction in renal inflammation and renal lymphangiogenesis during acute transplant rejection, suggesting that this treatment regimen is a valuable future treatment in renal transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Amides / therapeutic use
  • Animals
  • Chemokine CCL2 / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibrosis / immunology
  • Gene Expression Regulation / drug effects
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Graft Rejection / metabolism
  • Graft Rejection / physiopathology
  • Kidney Transplantation / adverse effects*
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / pathology
  • Lymphangiogenesis / drug effects*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Male
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Rats
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism

Substances

  • Amides
  • Ccl2 protein, rat
  • Chemokine CCL2
  • Protein Kinase Inhibitors
  • Pyridines
  • Y 27632
  • rho-Associated Kinases