Isoquercitrin Improves Renal Tubular Epithelial Cell Mitochondrial Dysfunction by Regulating Extracellular Signal‐Regulated Kinase/Reactive Oxygen Species Signaling and Connexin 43 Expression in Diabetic Kidney Disease

Isoquercitrin (IQ) is a natural flavonoid compound with potent anti-inflammatory and antioxidant effects; its role and mechanism of action in diabetic kidney disease (DKD) are unclear. This study clarified the role of IQ in delaying DKD and regulating tubular epithelial cell lipid metabolism. db/db mice were randomly divided into DKD, low-dose IQ, high-dose IQ, and dapagliflozin groups. C57BL/6J mice were used as controls. NRK-52E cells and connexin 43 (Cx43) knockdown (Cx43^+/-) cells were incubated with IQ and bovine serum albumin (BSA) in vitro. A cell counting kit-8 (CCK-8) was used to assess cell viability and a reactive oxygen species (ROS) detection kit was used to detect oxidative stress levels. Mitochondrial function was assessed using transmission electron microscopy, fluorescence staining, and an ATP assay. Western blotting was used to assess the levels of relevant proteins. IQ ameliorated renal dysfunction in db/db mice, and proteomic analysis indicates its mechanism involves the regulation of lipid metabolism and mitochondrial function. BSA increased ROS generation, enhanced fluorescence, decreased ATP content, and increased the expression of phosphorylated extracellular signal-regulated kinase (p-ERK), Cx43, and cluster of differentiation 36 (CD36) in NRK-52E cells; these effects were ameliorated by IQ. After Cx43^+/- NRK cells were incubated with BSA, the ROS/O₂ ^- fluorescence intensity and p-ERK expression were lower than those in wildtype NRK-52E cells. IQ delayed the occurrence and development of DKD by modulating mitochondrial lipid metabolism through the inhibition of Cx43 expression and ERK phosphorylation. This study provides valuable insights for the pharmacological treatment of DKD.