Question: 

Renal ischemia-reperfusion injury (IRI) typically develops as a result of surgery, transplantation or trauma. IRI is one of the main causes of acute renal failure, involving both the innate and adaptive immune response. Immune cells are attracted to the affected organ system and transmigrate into the interstitium. This is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the related reorganisation processes, mainly regulated by Rho GTPases, a preventive and selective inhibition of Rho effectors like the Rho-associated coiled-coil containing protein kinase (ROCK) may improve renal IRI outcome.

Methodology: 

One week before inducing 45 min. of warm ischemia by clamping the left renal artery, male Sprague Dawley rats underwent unilateral nephrectomy of the right kidney. One hour before ischemia animals received either 10 mg/kg hydroxyfasudil or an equivalent volume of isotonic NaCl as intraperitoneal injection. Post surgery the animals were kept in metabolic cages for 1–4 days (POD1-4); blood and urine samples were taken daily for analysis. Microarray analysis was performed on kidneys of both groups, harvested on POD4, as well as on kidneys of uninephrectomized and healthy animals.

Results: 

Hydroxyfasudil-treated animals showed reduced proteinuria and polyuria, as well as a lower decrease in urine osmolarity compared with untreated ischemic animals. In addition, creatinine- and urea-clearance improved significantly. Microarray analysis showed distinct alterations in the renal gene expression profile after IRI, which were reduced effectively by ROCK-inhibition. Compared with uninephrectomized animals 1115 genes were differentially expressed in untreated ischemic animals, while only 116 genes were affected after ROCK-inhibition. Among others, genes related to cell-cell signaling (151 genes), cellular movement (144 genes), cell death (200 genes), inflammatory responses (123 genes) and immune cell trafficking (84 genes) were overrepresented.

Conclusion: 

Hydroxyfasudil-mediated ROCK-inhibition is paralleled by improved kidney function, as well as a substantial reduction in the alteration of the renal gene expression profile. Therefore, ROCK-inhibition is a potential therapeutic target in human renal IRI.