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Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection.
Eur J Pharmacol. 2012 Nov 05; 694(1-3):111-9.EJ

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.

Authors+Show Affiliations

Department of Pathology & Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22964464

Citation

Poosti, Fariba, et al. "Targeted Inhibition of Renal Rho Kinase Reduces Macrophage Infiltration and Lymphangiogenesis in Acute Renal Allograft Rejection." European Journal of Pharmacology, vol. 694, no. 1-3, 2012, pp. 111-9.
Poosti F, Yazdani S, Dolman ME, et al. Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection. Eur J Pharmacol. 2012;694(1-3):111-9.
Poosti, F., Yazdani, S., Dolman, M. E., Kok, R. J., Chen, C., Ding, G., Lacombe, M., Prakash, J., van den Born, J., Hillebrands, J. L., van Goor, H., & de Borst, M. H. (2012). Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection. European Journal of Pharmacology, 694(1-3), 111-9. https://doi.org/10.1016/j.ejphar.2012.08.010
Poosti F, et al. 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. PubMed PMID: 22964464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection. AU - Poosti,Fariba, AU - Yazdani,Saleh, AU - Dolman,M Emmy M, AU - Kok,Robbert Jan, AU - Chen,Cheng, AU - Ding,Guohua, AU - Lacombe,Marie, AU - Prakash,Jai, AU - van den Born,Jacob, AU - Hillebrands,Jan-Luuk, AU - van Goor,Harry, AU - de Borst,Martin H, Y1 - 2012/09/03/ PY - 2012/02/05/received PY - 2012/08/22/revised PY - 2012/08/27/accepted PY - 2012/9/12/entrez PY - 2012/9/12/pubmed PY - 2013/4/6/medline SP - 111 EP - 9 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 694 IS - 1-3 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/22964464/Targeted_inhibition_of_renal_Rho_kinase_reduces_macrophage_infiltration_and_lymphangiogenesis_in_acute_renal_allograft_rejection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(12)00721-2 DB - PRIME DP - Unbound Medicine ER -