Abstract
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 urea-clearances 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.
Highlights
AKI is a critical clinical condition associated with a high degree of morbidity and mortality despite best supportive care
We show that several mechanisms contributed to the observed Rho-associated coiled coil containing protein kinase (ROCK)-dependent IRI changes, including changes in the expression of endothelial adhesion molecules, matrix metalloproteinases and increased endothelial leakage/vascular permeability accompanied by leukocyte recruitment and transmigration
By analyses of marker genes of leukocyte subpopulations, we observed in untreated post-ischemic kidneys a distinct up-regulation of marker mRNA of B-cells (CD20), neutrophil granulocytes (CD66a), activated B-cells/monocytes (CD80/B7-1), antigen presenting cells (CD86) and the monocyte/macrophage activity marker ficolin B (Fcnb)
Summary
AKI is a critical clinical condition associated with a high degree of morbidity and mortality despite best supportive care. IRI is one of the main causes of AKI. It occurs in a broad spectrum of clinical settings including (transplantation) surgery, trauma, dehydration or sepsis leading to renal hypoperfusion, acute tubular necrosis (ATN), and functional disturbances namely AKI. In renal transplantation it is a well known risk factor for delayed graft function, which prolongs hospitalization, increases costs, and needs a greater complexity of immunosuppressive drug management. Because IRI affects the kidney by reducing the number of nephrons and increases the risk of acute rejection episodes, it might cause a reduced graft survival
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