Repositioning of Ticagrelor: Renoprotection mediated by modulating renin-angiotensin system, inflammation, autophagy...

Aside from being an antiplatelet, ample studies revealed the anti-ischemic cardioprotective effect of Ticagrelor (Tica) mediated via different mechanisms; however, its protective potential against renal ischemia reperfusion (I/R) has been rarely investigated, which is the aim of the current study. Animals were divided into sham, I/R (45 min/24 h) and I/R pretreated with Tica (30 mg/kg) for one week, after a pilot study using 30 and 150 mg/kg of Tica. The pre-administration of Tica (30 mg/kg) guarded against the harmful impact of I/R insult and improved renal histological structure and function validated by reducing cystatin-C, neutrophil gelatinase-associated lipocalin, interleukin-18 and the classical markers, blood urea nitrogen and creatinine. On the molecular level, Tica signified its anti-inflammatory capacity by inhibiting nuclear factor κB and tumor necrosis factor-α, while it enhanced the autophagy process evidenced by increasing the protein expression of Beclin-1 and microtubule-associated protein light chain 3 II and abating the lysosomal marker cathepsin-D. Besides, Tica augmented cell survival by inhibiting galectin-3 and caspase-3 activity. Additionally, Tica modulated the renin-angiotensin system (RAS), where it decreased angiotensin II and downregulated the gene expression of prorenin and endothelin-1_A receptors, but increased the activity of angiotensin converting enzyme-2 and the renal content of angiotensin 1-7. Our study is the first to highlight the renal anti-ischemic potential of Tica via enhancing autophagy, modulating the RAS, and decreasing both inflammation and cell demise.