الفهرس 
Effect of a Mas receptor agonist on remote organ injury in a rat model of hind- limb ischemia / reperfusion Code (PO 3.4.2)
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Abstract
Hindlimb I/R (I/R) injury drives systemic inflammation that elicits remote organ damage of the liver, then it escalates due to the severe inflammatory response and the release of reactive oxygen species towards other body organs to cause multiple organ dysfunction syndrome. The activation of angiotensin 1-7/Mas receptor/Slit3/ROCK axis that mobilizes bone marrow progenitor cells (BMPCs) plays an indispensable role in vascular repair in experimental diabetopathy and after ischemic injury, besides hepatic progenitor cells (HPCs) incite hepato-cellular regeneration after liver perturbation. The current study aims to investigate the curative effect of chloroquine as a treatment strategy on the liver tissue as a collateral damage for hindlimb ischemia/reperfusion on the inflammatory, oxidative, autophagic and apoptotic process. The rats were divided into three groups, where the first is the control group, the second was subjected to hindlimb ischemia by wrapping around one hindlimb an orthodontic rubber band for
1.5 hours, then the reperfusion took place for the next seven days, and the third was subjected to the same terms of ischemia, however, at the start of the reperfusion period, chloroquine was administered (45 mg/kg/day; i.p). on the morning of the eighth day, the blood samples were taken, and the rats were euthanized, where the liver were taken for further biochemical, histopathological, and histochemical investigation. The results of the induction group showed a flare of the inflammatory pathway, where there was a hike in the levels of the tumor necrosis factor-alpha, p38-mitogen activated protein kinase, nuclear factor kappa B, and nitric oxide; on the contrary, the anti-inflammatory mediator level was declined. The oxidative stress markers were raised such as malonaldehyde, 8-; as for the total antioxidant capacity, it was decreased. Regarding, the autophagic process, it was initiated in the liver as a result for the induced hindlimb ischemia/reperfusion; it was manifested by the increase of the Beclin-1, LC3 I, LC3 II, and cathepsin-D hepatic level content. Furthermore, the apoptosis was also triggered showing a surge of Bax, and Caspase 3, meanwhile a downturn of the Bcl-2. On the other hand, the third group has showed opposite results of which had been recorded in the second one. It also aimed to investigate the potential regenerative effect of chloroquine and its involvement with Mas receptor in the liver, identified as a remote hindlimb I/R target organ. Accordingly, rats underwent unilateral 90 min hindlimb ischemia; then, animals were left untreated or treated for 7 days with chloroquine without or with the selective Mas receptor antagonist (A779); reperfusion was established for 8 days. Chloroquine enhanced the liver function marked by reductions in ALT&AST and abated the structural
changes induced by the hindlimb I/R injury. The drug increased the percentage of hepatic CD34+ cells quantified by flow cytometry, as well as its contents of CD133, VEGFR2, and AFP. It also activated the Slit3/Robo 1/ROCK and SDF-1 & VEGF/AKT hubs associated by enhanced CD31+ and PCNA immunoreactivity in the liver. On the contrary, the pre- administration of A779 completely blocked the effect of chloroquine on all parameters except for AKT and ROCK that showed a partial antagonism. To summarize our findings, this study proves the anti-inflammatory and antioxidant properties of chloroquine in response to the harmful effects of hindlimb ischemia/reperfusion the hepatic tissue. As well as its actions on halting the autophagy and apoptosis of the hepatic cells leading to an amelioration of the hepatic tissue against the remote insult. Moreover, chloroquine, Mas receptor dependently, lessened the hindlimb I/R associated hepatic injury via activating the Slit3/Robo1/ROCK and VEGF/VEGFR2 & SDF-1/AKT trajectories which effectively participated in the homing of EPCs and HPCs to the injured site to instigate hepatocyte proliferation and regenerative neovascularization mechanisms