ticagrelor and Acute-Kidney-Injury

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

Topics: Acute Kidney Injury; Animals; Autophagy; Dose-Response Relationship, Drug; Drug Repositioning; Galectin 3; Inflammation; Kidney; Platelet Aggregation Inhibitors; Protective Agents; Rats; Receptor, Endothelin A; Renin; Renin-Angiotensin System; Reperfusion Injury; Ticagrelor

Ticagrelor is a widely used anti-platelet drug. However, the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury (AKI) have not been clearly demonstrated. We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.. C57BL6J mice received oral ticagrelor (20 mg/kg and 50 mg/kg) for 7 days, and then caecal ligation and puncture (CLP) were performed. An adenosine receptor antagonist, CGS15943, was administered (10 mg/kg, intraperitoneal injection) to block the adenosine pathway 2 h before CLP. After 24 h, serum creatinine levels were measured. Periodic acid-Schiff (PAS) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were employed to analyze pathological changes and cell apoptosis. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and mRNA expression of tissue TNF-α and IL-1β were detected. Western blotting analysis was used to determine AKT and mammalian target of rapamycin (mTOR) protein expression in the kidney.. PAS staining showed less swelling of renal tubules, and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group. Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group. Moreover, significantly lower serum and kidney levels of TNF-α and IL-1β were observed in the ticagrelor group. CGS15943 blocked the effects of ticagrelor. Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group. The adenosine receptor antagonist inhibited the activation of AKT and mTOR.. This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.

Topics: Acute Kidney Injury; Animals; Creatinine; Mammals; Mice; Proto-Oncogene Proteins c-akt; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Sepsis; Ticagrelor; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Topics: Acute Kidney Injury; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rhabdomyolysis; Rosuvastatin Calcium; Ticagrelor

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Guanine Nucleotide Exchange Factors; Ischemia; Kidney Function Tests; Male; Purinergic P2Y Receptor Antagonists; rap1 GTP-Binding Proteins; Rats; Rats, Wistar; Renal Circulation; Reperfusion Injury; Signal Transduction; Ticagrelor

Platelets are traditionally considered to be essential components of primary hemostasis. Recent investigations have revealed that platelets can be activated in patients with sepsis and are implicated in the development of sepsis and sepsis-induced-acute kidney injury (SAKI). In the present study, ticagrelor was used to induce a mouse model of SAKI by cecal ligation and puncture. It was found that ticagrelor could inhibit platelet activity, decrease the levels of interleukin-1β and serum creatinine, reduce infiltration of neutrophils in renal tissue, and attenuate cell apoptosis in the kidney. The results suggested that ticagrelor could protect renal function by inhibiting inflammation, recruitment of neutrophils into the kidney, and cell apoptosis in renal tissue. Thus, the findings might provide new strategies for preventing SAKI.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Humans; Male; Mice; Platelet Aggregation Inhibitors; Sepsis; Ticagrelor

Topics: Acute Kidney Injury; Administration, Oral; Aged, 80 and over; Coronary Artery Disease; Diagnosis, Differential; Female; Humans; Nausea; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Rhabdomyolysis; Ticagrelor; Vomiting

Renal function deterioration is a rather frequent side effect of ticagrelor; this is especially so in patients over the age of 75, with pre-existent mild renal failure and/or taking an angiotensin receptor inhibitor. We describe a patient in whom deterioration of renal function due to ticagrelor led to a rise in serum concentration of rosuvastatin which resulted in rhabdomyolysis. The presented case emphasises the importance to check renal function routinely before and one month after starting ticagrelor and to screen carefully for possible interactions with other drugs.

Topics: Acute Kidney Injury; Adenosine; Aged; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Rhabdomyolysis; Rosuvastatin Calcium; Ticagrelor