Adropin Carried by Reactive Oxygen Species-Responsive Nanocapsules Ameliorates Renal Lipid Toxicity in Diabetic Mice

Diabetic kidney disease (DKD) is a common diabetes complication mainly caused by lipid toxicity characterized by oxidative stress. Studies have shown that adropin (Ad) regulates energy metabolism and may be an effective target to improve DKD. This study investigated the effect of exogenous Ad encapsulated in reactive oxygen species (ROS)-responsive nanocapsules (Ad@Gel) on DKD. HK2 cells were induced with high glucose (HG) and intervened with Ad@Gel. A diabetes mouse model was established using HG and high-fat diet combined with streptozotocin and treated with Ad@Gel to observe its effects on renal function, pathological damage, lipid metabolism, and oxidative stress. Results showed that Ad@Gel could protect HK2 from HG stimulation in vitro. It also effectively controls blood glucose and lipid levels, improves renal function, inhibits excessive production of ROS, protects mitochondria from damage, improves lipid deposition in renal tissues, and downregulates the expression of lipogenic proteins SEBP-1 and ADRP in DKD mice. In HG-induced HK2 cells or the kidney of DKD patients, the low expression of neuronatin (Nnat) and high expression of translocator protein (TSPO) were observed. Knockdown Nnat or overexpression of TSPO significantly reversed the effect of Ad@Gel on improving mitochondrial damage. In addition, knockdown Nnat also significantly reversed the effect of Ad@Gel on lipid metabolism. The results suggest that the effect of Ad on DKD may be achieved by activating Nnat to improve lipid metabolism and inhibit TSPO activity, thereby enhancing mitochondrial function.