Acid Ceramidase as a Novel Target for Adiponectin Receptor Agonist to Abrogate NLRP3 Inflammasome Activation and Glomerular Injury during Obesity

Adiponectin receptor agonists have recently been reported to protect against glomerular inflammation and injury during obesity. Nevertheless, the molecular mechanism underlying their protective action against obesity-related glomerulopathy (ORG) remains poorly understood. Given the implication of ceramide signaling pathway in the pathogenesis of ORG, the present study tested whether adiponectin receptor agonists target lysosomal acid ceramidase (AC) to inhibit NLRP3 inflammasome activation and glomerular injury during obesity. Confocal microscopy showed that NLRP3 inflammasome activation induced by visfatin, a pro-inflammatory adipokine, in murine podocytes was remarkably attenuated by adiponectin. Also, it was found that adiponectin significantly inhibited visfatin-induced formation of multivesicular bodies (MVBs) containing IL-1β in podocytes. Such inhibitory effect of adiponectin was abolished by AC inhibitors (carmofur and ARN14974) but mimicked by genistein (AC inducer) or MCC950 (NLRP3 inflammasome inhibitor). By nanoparticle tracking analysis, we measured exosomes released from podocytes in different groups, which have been reported to mediate the secretion of NLRP3 inflammasome products to extracellular space to activate inflammatory response. Visfatin-induced elevation of exosome release from podocytes was remarkably suppressed by adiponectin. This action of adiponectin was blocked by AC inhibitors but mimicked by genistein. In vivo, we showed that high-fat diet-induced T cell infiltration in glomeruli was exaggerated by podocyte-specific Smpd1 gene (gene code of acid sphingomyelinase) overexpression in Smpd1trg/Podocre mice compared to WT/WT mice. However, intraperitoneal injection of AdipoRon, a synthetic adiponectin receptor agonist, significantly decreased obesity-induced glomerular inflammatory response in both WT/WT and Smpd1trg/Podocre mice. Such anti-inflammatory effect of AdipoRon was prevented by co-treatment with carmofur. Moreover, podocyte-specific Smpd1 gene overexpression amplified HFD-induced podocyte injury, proteinuria, and glomerular sclerosis in Smpd1trg/Podocre mice compared to control littermates. These pathological changes were prevented by AdipoRon, and the effect of AdipoRon was reversed by carmofur. Taken together, our findings suggest that activation of AC signaling pathway mediates the protective action of adiponectin receptor agonists against glomerular inflammation and injury in ORG. This study was supported by NIH grants DK054927 and DK120491. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.