Demotion of canonical/non-canonical inflammasome and pyroptosis alleviates ischemia/reperfusion-induced acute kidney injury: Novel role of the D2/D3 receptor agonist ropinirole

Abstract

Ropinirole used to treat Parkinson's disease highly targets the dopaminergic receptor D3 over the D2 receptor but although both are expressed in the kidneys the ropinirole potential to treat kidney injury provoked by ischemia/reperfusion (I/R) is undraped. We investigated whether ropinirole can alleviate renal I/R by studying its anti-inflammatory, antioxidant, and anti-pyroptotic effects targeting its aptitude to inhibit the High-mobility group box 1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF-κB) cue and the canonical/non-canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome trajectories. Herein, bilateral I/R surgery was induced in animals to be either untreated or treated with ropinirole for three days after the insult. Ropinirole successfully improved the histopathological picture and renal function which was confirmed by reducing cystatin C and the standard parameters creatinine and blood urea nitrogen (BUN). Ropinirole achieved this through its anti-inflammatory capacity mediated by reducing the HMGB1/TLR4 axis and inactivating NF-κB, which are upstream regulators of the NLRP3 pathway. As a result, the injurious inflammasome markers (NLRP3, apoptosis-associated speck-like protein (ASC), active caspase-1) and their target cytokines interleukin-1 beta (IL-1β) and IL-18 were decreased. Ropinirole also reduced the pyroptotic cell death markers caspase-11 and gasdermin-D. Furthermore, ropinirole by replenishing antioxidants and decreasing malondialdehyde helped to reduce oxidative stress in the kidneys. The docking findings confirmed that ropinirole highly binds to the dopaminergic D3 receptor more than to the D2 receptor. In conclusion, ropinirole has the potential to be a reno-therapeutic treatment against I/R insult by abating the inflammatory NLRP3 inflammasome signal, pyroptosis, and oxidative stress.