Nephroprotective Effect of Serelaxin in Ischemia/Reperfusion Injury in Rat by Suppressing of TLR2-IL-1β/MCP-1 Signaling Pathway and Apoptosis

Ischemia reperfusion injury (IRI) is the net result of an inflammatory process which occurred when an organ suffering from a transient decrease or cessation of the blood flow, followed by restoration of perfusion. The kidney is considered as one of the most susceptible organ to IRI. IRI is considered one of the major challenge of organ transplantation, because it directly correlates to the graft rejection. Oxidative stress is an important pathway that participate in the pathogenesis of IRI through enhancing of ROS production. ROS react with cellular component leading to lipid peroxidation, inactivation of the enzyme, oxidation of glutathione, formation of organic radical, and destruction of the cell. The inflammation and immune system play a serious function in the pathogenesis of renal IRI. Renal IR up regulates the gene expression of TLR in parts of kidney. Activation of these receptors lead to enhancement of inflammatory mediators which induce inflammatory responses, resulting in tubulointerstitial injury. Serelaxin has anti-inflammatory, antifibrotic, antihypertrophic, and cytoprotective effects. Serelaxin decrease infiltration of the inflammatory cells such as neutrophils, basophils, mast cells and macrophage to several injured or damaged tissues and decrease the cytokines and chemokine released by these cells. This study aimed to investigate the potential effect of serelaxin in renal IRI in rat model by targeting TLR signaling pathway and their downstream proinflammatory cytokine and chemokine and caspase3. Twenty adult male of Sprague Dawley rats were randomized into four equal groups: sham group (underwent laparotomy but without IR, N = 5), control group (rats subjected to 30 min ischemia and 2 h reperfusion, N = 5), vehicle group (same as in control group + distilled water, N = 5), serelaxin group (as in control + 5 mu g/kg SLX, N = 5). The kidney and blood were harvested after 2 h of reperfusion. Blood sample used to assessment SU and Scr. Kidney used to assess tissue IL-1, MCP1, caspase3 and TLR2 as well as the histological examination. Rats in control and vehicle groups observed a significant increase in SU, Scr, caspase3, IL-1 beta, MCP-1, and TLR2 comparing with sham group. Histopathologically, the study showed a significant elevation in injury score. Kidneys of serelaxin pretreated rats demonstrated histological and functional improvement as evidenced by significant decreased in SU and Scr, MCP-1, IL-1 beta, and TLR2 in pretreated group appeared significantly reduced compared with control and vehicle groups. Serelaxin diminished the kidney damage mediated by renal ischemia and reperfusion. This renoprotective effect may be achieved by modulation of inflammatory response through inhibition of TLR2 signaling pathway and reduce its downstream IL-1 beta and MCP-1 protein expression in addition to antiapoptotic effect.