Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase

Abstract

Chemokines are important players in the migration of leukocytes to sites of injury and are also involved in angiogenesis, development and wound healing. In this study, we performed microarray analyses to identify chemokines that play a role during the inflammatory and repair phase after renal ischemia/reperfusion (I/R) injury and investigated the temporal relationship between chemokine expression, leukocyte accumulation and renal damage/repair. C57Bl/6 mice were subjected to unilateral ischemia for 45 min and sacrificed 3 h, 1 day and 7 days after reperfusion. From ischemic and contralateral kidney, RNA was isolated and hybridized to a microarray. Microarray results were validated with quantitative real-time reverse transcription–PCR (QRT–PCR) on RNA from an independent experiment. (Immuno)histochemical analyses were performed to determine renal damage/repair and influx of leukocytes. Twenty out of 114 genes were up-regulated at one or more reperfusion periods. All these genes were up-regulated 7 days after I/R. Up-regulated genes included CC chemokines MCP-1 and TARC, CXC chemokines KC and MIP-2α, chemokine receptors Ccr1 and Cx3cr1 and related genes like matrix metalloproteinases. Microarray data of 1 and 7 days were confirmed for 17 up-regulated genes by QRT–PCR. (Immuno)histochemical analysis showed that the inflammatory and repair phase after renal I/R injury take place after, respectively, 1 and 7 days. Interestingly, chemokine expression was highest during the repair phase. In addition, expression profiles showed a biphasic expression of all up-regulated CXC chemokines coinciding with the early inflammatory and late repair phase. In conclusion, we propose that temporal expression of chemokines is a crucial factor in the regulation of renal I/R injury and repair.

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

“…One day after reperfusion, the time point at which neutrophil influx peaks, 5 chimeric mice in which leukocytes were Nlrp3 deficient did not show reduced renal damage 15 and function (this study). Therefore, we speculated that Nlrp3 in macrophages, of which influx peaks at day 5, 10 rather than neutrophils is important for differences in renal damage in the late phase of renal IR injury.…”

“…2 After injury, wounded tissue organizes an efficient response that aims to combat infections, clear cell debris, re-establish cell number, and reorganize tissue architecture. First, necrotic tissue releases dangerassociated molecular patterns, such as high-mobility group box-1 3 or mitochondrial DNA, 4 which leads to chemokine secretion 5 and a subsequent influx of leukocytes. Second, neutrophils and macrophages clear cellular debris but also increase renal damage because depletion of neutrophils 6 or macrophages within 48 hours of IR will reduce renal damage.…”

Tamm-Horsfall protein-deficient thick ascending limbs promote injury to neighboring S3 segments in an MIP-2-dependent mechanism

“…MIP-2 is expressed in the kidney (31), and induced with injury (22,36,40), but its specific tubular localization has not been well-defined. The role of MIP-2 in the recruitment of neutrophils after kidney injury has been previously studied by Miura and colleagues (23), where neutralization of MIP-2 by specific antibodies in a mouse model of ischemia-reperfusion reduced neutrophil infiltration and attenuated kidney injury (23).…”

“…This chemokine is thought to play an important role in neutrophil recruitment to the site of injury during AKI (22,23,40). Although MIP-2 expression is induced after ischemiareperfusion (36), its specific tubular localization has not been well-defined in the context of AKI.…”

Lysophosphatidic Acid and Lovastatin Might Protect Kidney in Renal I/R Injury by Downregulating MCP-1 in Rat

“…Animal experiment and clinical observations have indicated that under the conditions of ischemia, hypoxia, intoxication, inflammation, and allergic reaction, expression of MCP-1 is elevated. 7,8 MCP-1/CCR2 signaling contributes to the pathogenesis of renal I/R injury, 9 and blockage of the signaling rescues renal I/R injury. 10 In rat renal I/R injury, cytokine KC and MIP-2 are also upregulated.…”