Mulberry Leaf Extract and Its Constituent Kuwanon C Show Therapeutic Potential toward Diabetic Nephropathy, with Associated Modulation of Oxidative Stress and Inflammation

Abstract This study aims to investigate the therapeutic potential and underlying mechanism of mulberry leaf extract (MLE) and its major constituent toward diabetic nephropathy (DN). Oral administration of an MLE fraction (MLE-3) markedly improved the physiological indicators and renal histological injuries of DN mice. Transcriptomic analyses revealed that the anti-DN effect of MLE-3 could be associated with its modulation of oxidative stress and inflammation, which was confirmed by further evaluations in both HK-2 and RAW264.7 cells. Mechanistically, the beneficial effect of MLE-3 on DN was likely related to the restoration of redox homeostasis via the Keap1-Nrf2 pathway, regulation of macrophage polarization, and inhibition of the NF-κB-NLRP3 signaling axis. Moreover, the anti-inflammatory property of MLE-3 was well phenocopied by its primary constituent kuwanon C via inhibition of NF-κB-NLRP3 axis activation in both cell models. Overall, this study provides a theoretical foundation for the development of mulberry leaf-based functional food products for DN management.