Inhibition of renal Rho kinase attenuates ischemia/reperfusion-induced injury

Jai Prakash*, Martin H. De Borst, Marie Lacombe, Frank Opdam, Pieter A. Klok, Harry Van Goor, Dirk K.F. Meijer, Frits Moolenaar, Klaas Poelstra, Robbert J. Kok

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    55 Citations (Scopus)

    Abstract

    The Rho kinase pathway plays an important role in dedifferentiation of epithelial cells and infiltration of inflammatory cells. For testing of the hypothesis that blockade of this cascade within the kidneys might be beneficial in the treatment of renal injury the Rho kinase inhibitor, Y27632 was coupled to lysozyme, a low molecular weight protein that is filtered through the glomerulus and is reabsorbed in proximal tubular cells. Pharmacokinetic studies with Y27632-lysozyme confirmed that the conjugate rapidly and extensively accumulated in the kidney. Treatment with Y27632-lysozyme substantially inhibited ischemia/reperfusion-induced tubular damage, indicated by reduced staining of the dedifferentiation markers kidney injury molecule 1 and vimentin, and increased E-cadherin relative to controls. Rho kinase activation was inhibited by Y27632-lysozyme within tubular cells and the interstitium. Y27632-lysozyme also inhibited inflammation and fibrogenesis, indicated by a reduction in gene expression of monocyte chemoattractant protein 1, procollagen Iα1, TGF-β1, tissue inhibitor of metalloproteinase 1, and α-smooth muscle actin. Immunohistochemistry revealed reduced macrophage infiltration and decreased expression of α-smooth muscle actin, collagen I, collagen III, and fibronectin. In contrast, unconjugated Y27632 did not have these beneficial effects but instead caused systemic adverse effects, such as leukopenia. Neither treatment improved renal function in the bilateral ischemia/reperfusion model. In conclusion, the renally targeted Y27632-lysozyme conjugate strongly inhibits tubular damage, inflammation, and fibrogenesis induced by ischemia/reperfusion injury.

    Original languageEnglish
    Pages (from-to)2086-2097
    Number of pages12
    JournalJournal of the American Society of Nephrology
    Volume19
    Issue number11
    DOIs
    Publication statusPublished - 1 Nov 2008

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