Huaier Attenuates Renal Injury in Type 2 Diabetic Nephropathy by Ameliorating Mitochondrial Dysfunction and Inhibiting Tubular Epithelial Cell Apoptosis

BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of Type 2 diabetes, with renal tubular epithelial cells (RTECs) apoptosis playing a pivotal role in its progression. The aqueous extract of Trametes robiniophila Murr. (Huaier) has shown renoprotective effects, but its specific molecular mechanisms in DN remain to be fully elucidated. OBJECTIVE: This study aimed to investigate the therapeutic effects of Huaier aqueous extract on DN and verify whether its anti-apoptotic mechanism is mediated through the Wnt/β-catenin pathway using the pathway activator SKL2001. METHODS: In vivo, KKAy Type 2 diabetic mice were treated with Huaier (5 g/kg/day) for 12 weeks to evaluate renal function and histopathology. In vitro, HK-2 cells were treated with high glucose and palmitate (HG + PA) to induce injury. The Wnt/β-catenin pathway activator SKL2001 was employed to determine if activating this pathway could abolish the protective effects of Huaier. RESULTS: Bioinformatics analysis indicates that the regulation of apoptosis is the primary mechanism by which Huaier improves DN. In vivo, Huaier reduced UACR and improved renal histopathology in KKAy mice. Consistently, TUNEL staining and molecular analysis confirmed that Huaier significantly suppressed RTECs apoptosis within the renal tissues. In vitro experiments demonstrated that Huaier significantly inhibited HG + PA-induced oxidative stress, mitochondrial dysfunction, and RTECs apoptosis. Notably, the administration of SKL2001 effectively reversed these protective effects, leading to increased β-catenin expression and elevated apoptosis levels despite Huaier treatment. CONCLUSION: Huaier aqueous extract mitigates RTECs apoptosis and renal injury in Type 2 diabetic nephropathy by suppressing the Wnt5a/β-catenin signaling pathway.