Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2^−/−) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the β-adrenergic receptor (β-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2^−/− mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2^−/− mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Introduction: Membranous nephropathy constitutes a significant proportion of cases leading to end-stage renal disease. In such instances, the accurate distinction between primary and secondary forms is crucial for proper treatment. Consequently, we systematically examined the link between genetically predicted membranous nephropathy and various diseases. Methods: The phenome-wide association approach assessed the links between genetically predicted membranous nephropathy and 2,408 diseases. Two-sample Mendelian randomization was then employed to explore causal relationships using methods like inverse variance weighting, MR-Egger, weighted median, and others. A replication analysis was conducted to confirm these associations. Gene enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses to explore potential pathogenic mechanisms. Results: A statistically significant association was noted between genetically predicted Graves’ disease, thyrotoxicosis, and thyrotoxicosis with diffuse goiter and an elevated risk of membranous nephropathy. Subsequent replication analysis for Graves’ disease demonstrated consistent results. Functional analysis suggests that Graves’ disease may affect membranous nephropathy by influencing pathophysiological mechanisms and pathways related to the proliferation and differentiation of lymphocytes and leukocytes, adhesion between leukocytes and cells, differentiation of CD4+ αβ T cells, and differentiation of Th1 and Th2 cells. Conclusion: Our study indicates that genetically predicted thyrotoxicosis, thyrotoxicosis with diffuse goiter, and Graves’ disease are correlated with an increased likelihood of membranous nephropathy. Graves’ disease may affect membranous nephropathy development by influencing leukocyte proliferation and differentiation. Additional research is warranted to validate these findings and ascertain their relevance in clinical management.