Acute renal injury (AKI) is triggered by different factors, but the chief reason is ischemia/reperfusion (I/R) accompanied by a high rate of mortality and morbidity (Eltzschig and Collard, 2004); Beach et al., 2020). The renal I/R pathogenesis induces an inflammatory cascade, tubular epithelial cell death, and oxidative stress (Padanilam, 2003). As the blood reperfusion phase ensues, the dented cells liberate high-mobility group box 1 (HMGB1) which acts as an endogenous inflammatory mediator to bind the inflammatory target receptors of advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) ending by the nuclear translocation/activation of nuclear factor-kappa (NF-κ)B (Wu et al., 2014). This trail (signal 1) is responsible for the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome priming/stimulation (Chen et al., 2022). Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) (Swanson et al., 2019), are among the alarmins that activate NF-κB to aid in the NLRP3 priming step (Liu et al., 2017) initiating both an inflammatory cascade (canonical inflammasome) and apoptotic cell demise (non-canonical inflammasome) (Gan et al., 2022). In the canonical type, ASC and caspase-1 assemble with NLRP3 to activate the immature cytokines pro-IL-1β, and pro-IL-18 (Juliana et al., 2012) The latter cascade can be provoked by signal 2 by sensing PAMPs/DAMPs and reactive oxygen species (ROS) to activate the zymogen pro-caspase-1 into caspase-1. NLRP3 also activates the pyroptotic trajectory that encompasses the activation of caspase-11 (Kayagaki et al., 2011) which besides the stimulated caspase-1, triggers the pore-forming protein N-terminal cleaved gasdermin D (GSDMD-N) allowing the release of proinflammatory cytokines besides the endogenous PAMPs and DAMPs to keep the loop going (Platnich and Muruve, 2019; Chauhan et al., 2020).

Dopamine (D) receptors are classified into 5 subtypes (D1-D5) allocated into the D1-and D2-subfamilies where the first one includes both dopaminergic receptors D1 & D5, whereas the second encompasses the dopaminergic receptors D2-D4 (Seeman and Van Tol, 1994). The dopaminergic receptors are significantly distributed in different areas of the kidney embracing the glomeruli, and renal tubules besides renal vasculature (Cheung and Barrington, 1996; Luippold et al., 1998). Along with the eminent physiological role of the D1 and D2 receptors (Harris and Zhang, 2012), the D3 receptor subtype draws more interest due to its renal abundance and regulatory role in kidney function (Mühlbauer et al., 2000).

Ropinirole, a non-ergoline-dopamine receptor agonism, is approved by the FDA for treating restless legs syndrome besides Parkinson's disease (Varga et al., 2009). Ropinirole targets post-synaptic dopaminergic receptors D2/D3 with a higher affinity to the dopaminergic receptor D3 (Joyce and Millan, 2007). Along with its official indication, ropinirole offers neuroprotection against focal cerebral ischemic injury by reducing mitochondria-mediated ROS production (Andrabi et al., 2020) and presents a dopaminergic D3 receptor-dependent antiapoptotic activity in different neurotoxicity paradigms (Chen et al., 2008; Park et al., 2013).

Accordingly, we hypothesized that ropinirole can be repositioned to alleviate AKI. Thus, we scrutinized the potential therapeutic role of ropinirole after inducing the I/R rat model targeting the inflammatory canonical/non-canonical NLRP3 inflammasome, pyroptosis, and oxidative stress.