10. PAR4 as a dual player in acute kidney injury
Acute kidney injury (AKI) is one of the most common complications in hospitalized patients with an increased risk of mortality [112]. AKI can be contributed by various factors such as renal ischemia-reperfusion (I/R), with the activation of the coagulation system and inflammatory processes resulting in renal tissue remodeling and dysfunction [70,71]. Previously, studies revealed that PAR4 is present in both mice and human podocytes and also in proximal tubular epithelial cells [53,113]. Jansen et al [114] has investigated the role of PAR4 in the renal I/R injury model. In this study, post-renal IR insult resulted in up-regulation of PAR 4 gene expression in WT mice. However, it was observed that renal I/R injury resulted in the production of thrombin protease in both the WT and PAR4 knockout mice subjected to I/R injury. In addition, the expression of renal injury markers, KIM-1 and NGAL remained up-regulated in PAR 4 knockout mice post I/R injury insult, and also protein cast formation was evident in the tubular lumen. Previous studies have reported that inflammation is implicated in the pathology of renal I/R injury [70]. Jansen et al [114] in their study has demonstrated that PAR4 deletion following I/R injury decreased the neutrophil accumulation in renal tissue without having any impact on the pro-inflammatory cytokines, monocyte chemoattractant protein 1(MCP-1), or keratinocyte-derived chemokine expression. However, renal I/R injury in PAR4 absence resulted in podocyte effacement which produced proteinuria. As a whole PAR4 has exhibited a dual role in mediating renal I/R injury, as it has facilitated the progression of I/R induced renal injury by promoting neutrophil invasion and in contrast also responsible for maintaining the renal filtration barrier integrity. The observed discrepancies related to distinct effects of PAR4 on renal pathological outcomes in the I/R model could be explained by the fact that PAR4 triggers leukocyte recruitment during the diseased conditions, but might exhibit distinct effects on renal tissue [76]. Furthermore, the findings pertaining to the distinct effects of PAR4 subtype during I/R injury need to be confirmed in other renal disease models.