Methods: Data from the National Health and Nutrition Examination Survey (NHANES) were used for evaluating the association between dietary quercetin intake and all-cause mortality in patients with DKD.Ischemia/reperfusion (I/R)-induced AKI models in db/m and db/db mice, and Kidney epithelial cells exposed to high glucose with or without hypoxia/reoxygenation (HG + H/R) conditions were employed.Quercetin-loaded IR783 nanoparticles were synthesized and administered in vivo and in vitro.Gain-and loss-of-function approaches targeting PDK4 and oxidative stress regulators were applied to confirm mechanistic pathways.Renal function, histopathology, oxidative stress markers, and mitochondrial activity were evaluated.Results: Analysis of NHANES data revealed that higher dietary quercetin intake was significantly associated with the low all-cause mortality in DKD patients.Quercetin-loaded IR783 nanoparticles significantly reduced renal tubular injury and improved renal function in I/R -db/db mice compared with free quercetin or vehicle controls.In vitro, treatment with quercetin-loaded IR783 attenuated ROS accumulation, preserved mitochondrial membrane potential.Mechanistically, nanoparticle treatment suppressed PDK4 expression and downstream oxidative stress signaling, as demonstrated that overexpression of PDK4 abolished the protective effects, whereas PDK4 knockdown mimicked the benefits of nanoparticle treatment.Conclusion: Higher dietary quercetin intake is associated with reduced mortality in DKD patients, and quercetin encapsulated in IR783 nanoparticles protects against AKI in DKD by attenuating PDK4/ oxidative stress signaling.I have potential conflict of interest to disclose.
He et al. (Wed,) studied this question.