Mirabegron, dependent on β3-adrenergic receptor, alleviates mercuric chloride-induced kidney injury by reversing the impact on the inflammatory network, M1/M2 macrophages, and claudin-2

The beta 3-adrenergic receptor (beta 3-AR) agonism mirabegron is used to treat overactive urinary bladder syndrome; however, its role against acute kidney injury (AKI) is not unveiled, hence, we aim to repurpose mirabegron in the treatment of mercuric chloride (HgCl2)-induced AKI. Rats were allocated into normal, normal + mirabegron, HgCl2 untreated, HgCl2 + mirabegron, and HgCl2 + the beta 3-AR blocker SR59230A + mirabegron. The latter increased the mRNA of beta 3-AR and miR-127 besides downregulating NF-kappa B p65 protein expression and the contents of its downstream targets iNOS, IL-4, -13, and -17 but increased that of IL-10 to attest its anti-inflammatory capacity. Besides, mirabegron downregulated the protein expression of STAT-6, PI3K, and ERK1/2, the downstream targets of the above cytokines. Additionally, it enhanced the transcription factor PPAR-alpha but turned off the harmful hub HNF-4 alpha/HNF-1 alpha and the lipid peroxide marker MDA. Mirabegron also downregulated the CD-163 protein expression, which besides the inhibited correlated cytokines of M1 (NF-kappa B p65, iNOS, IL-17) and M2 (IL-4, IL-13, CD163, STAT6, ERK1/2), inactivated the macrophage phenotypes. The crosstalk between these parameters was echoed in the maintenance of claudin-2, kidney function-related early (cystatin-C, KIM-1, NGAL), and late (creatinine, BUN) injury markers, besides recovering the microscopic structures. Nonetheless, the pre-administration of SR59230A has nullified the beneficial effects of mirabegron on the aforementioned parameters. Here we verified that mirabegron can berepurposedto treat HgCl2-induced AKI by activating the beta 3-AR. Mirabegron signified its effect by inhibiting inflammation, oxidative stress, and the activated M1/M2 macrophages, events that preserved the proximal tubular tight junction claudin-2 via the intersection of several trajectories.