Hydroxyfasudil-Mediated Inhibition of ROCK1 and ROCK2 Improves Kidney Function in Rat Renal Acute Ischemia-Reperfusion Injury

Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune...

Authors: Kentrup, Dominik
Reuter, Stefan Johannes
Schnöckel, Uta
Grabner, Alexander
Edemir, Bayram
Pavenstädt, Hermann
Schober, Otmar
Schäfers, Michael
Schlatter, Eberhard
Büssemaker, Eckhart
Division/Institute:FB 05: Medizinische Fakultät
Document types:Article
Media types:Text
Publication date:2011
Date of publication on miami:21.02.2013
Modification date:05.09.2019
Edition statement:[Electronic ed.]
Source:PLoS ONE 6 (2011) 10, e26419
DDC Subject:610: Medizin und Gesundheit
License:CC BY 2.5
Language:English
Notes:Finanziert durch den Open-Access-Publikationsfonds 2011/2012 der Deutschen Forschungsgemeinschaft (DFG) und der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format:PDF document
URN:urn:nbn:de:hbz:6-77379454716
Permalink:http://nbn-resolving.de/urn:nbn:de:hbz:6-77379454716
Other Identifiers:DOI: doi:10.1371/journal.pone.0026419
Digital documents:journal.pone.0026419.pdf

Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the important role of cytoskeletal reorganization, mainly regulated by RhoGTPases, in the development of IRI we hypothesized that a preventive, selective inhibition of the Rho effector Rho-associated coiled coil containing protein kinase (ROCK) by hydroxyfasudil may improve renal IRI outcome. Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals. In addition, renal perfusion (as assessed by 18F-fluoride Positron Emission Tomography (PET)), creatinine- and ureaclearances improved significantly. Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, 18F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis. We conclude from our study that ROCK-inhibition by hydroxyfasudil significantly improves kidney function in a rat model of acute renal IRI and is therefore a potential new therapeutic option in humans.