Abstract

Acute kidney injury is a common ailment that ensues when the kidney is exposed to different insults, including ischemia/reperfusion (I/R), a disorder detected in cases of septic shock, cardiovascular surgery, and kidney transplantation and in addition it activates platelets to contribute more in renal injury. Ticagrelor, an antiplatelet that inhibits adenosine diphosphate (ADP)-mediated platelet aggregation via blocking of the purinergic receptor P2Y12, is known for its anti-ischemic cardioprotective capacity, but its renoprotective effect against I/R is rarely addressed, which is the aim of the current study.
Thus, adult male Wistar rats were allocated into 3 groups, namely sham-operated, I/R-operated (45 min/24 h) and I/R pretreated with Tica (30 mg/kg) for one week. Due to the scarce doses available in kidney injury models, a pilot study using 30 and 150 mg/kg of Tica was carried out and according to the obtained results, 30 mg/kg was chosen.
The pre-administration of Tica (30 mg/kg) for one week guarded against the harmful impact of I/R insult and improved renal histological structure and function, which was validated by the reduced cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 and the classical markers, blood urea nitrogen (BUN) and creatinine. The renin-angiotensin system (RAS) plays a critical role in the kidney and in our study Tica has reverted the effect of I/R on the RAS related markers, where it downregulated the gene expression of the receptors prorenin and endothelin-1A and eventually led to a reduction in the potent vasoconstrictor angiotensin (Ang) II. On the other hand, Tica heightened the beneficial molecules, where it increased the activity of angiotensin-converting enzyme-2 (ACE-2) and the renal content of angiotensin 1-7 (Ang 1-7). Apart from the RAS, Tica signified its anti-inflammatory capacity by inhibiting the inflammatory transcription factor nuclear factor κB (NF-κB) and the surrogate inflammatory marker tumor necrosis factor (TNF)-α. Additionally, Tica enhanced the autophagy flux machinery that was hindered by the I/R insult. Here, Tica increased the protein expression of Beclin-1 and microtubule-associated protein light chain 3 II (LC-3 II) and abated the lysosomal marker cathepsin-D. Besides, Tica augmented cell survival by inhibiting caspase-3 activity and galectin-3, which is known as a marker of cardiac and renal injury.
Our study is the first to highlight the renal anti-ischemic potential of Tica via modulating the RAS, enhancing autophagy, and decreasing both inflammation and cell demise to improve renal morphology and function in a model of renal I/R.

Biography

I am Hanan Salah Eldin El-Abhar, Chair of the Pharmacology, Toxicology & Biochemistry department at Faculty of Pharmacy, Future University in Egypt (FUE; 2018-till now) and was Chair of the Pharmacology & Toxicology department at Faculty of Pharmacy, Cairo University for 6 years (2011-2017). I am a peer reviewer for several international journals in my specialty and I have 81 international published articles (1995-2022) and an Editor at the journal of “Integrative Diabetes and Cardiovascular Diseases” and “Future Journal of Pharmaceutical Sciences [FJPS])”. I am a member of several Scientific Associations, a member of the judging and discussion panel for many Masters and Ph.D. theses, and a member of the Masters and Ph.D. degrees equivalence department at the sector of specialized pharmaceutical studies in the Supreme Council of Universities in Egypt. I was a Consultant at the Pharmacology Committee of the Central Agency of Pharmaceutical Affairs (CAPA) at the Egyptian Ministry of Health (2013-2015) and Managerial Secretary and member of the permanent scientific committee for the promotion of assistant professors and professors at the National Organization for Drug Control and Research (NODCAR, 2013-2015). I am one of the World’s Top 2% Scientists list (Stanford University, 2021).

X