RGD Reference Report - Inhibition of renal rho kinase attenuates ischemia/reperfusion-induced injury. - Rat Genome Database

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Inhibition of renal rho kinase attenuates ischemia/reperfusion-induced injury.

Authors: Prakash, J  De Borst, MH  Lacombe, M  Opdam, F  Klok, PA  Van Goor, H  Meijer, DK  Moolenaar, F  Poelstra, K  Kok, RJ 
Citation: Prakash J, etal., J Am Soc Nephrol. 2008 Nov;19(11):2086-97. doi: 10.1681/ASN.2007070794. Epub 2008 Jul 23.
RGD ID: 11526113
Pubmed: PMID:18650485   (View Abstract at PubMed)
PMCID: PMC2573003   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2007070794   (Journal Full-text)

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 Ialpha1, TGF-beta1, tissue inhibitor of metalloproteinase 1, and alpha-smooth muscle actin. Immunohistochemistry revealed reduced macrophage infiltration and decreased expression of alpha-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Kidney Reperfusion Injury treatmentISOCcl2 (Rattus norvegicus)11526113; 11526113 RGD 
Kidney Reperfusion Injury treatmentIDA 11526113 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Mus musculus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2)


Additional Information