Abstract
BACKGROUND: Diabetic nephropathy (DN), a severe complication of Type 2 diabetes mellitus (T2DM), is the primary reason of end-stage kidney disease (ESKD) and is closely associated with an elevated cardiovascular risk. While miR-484 has been implicated in diabetes, its specific role in DN remains to be elucidated. OBJECTIVE: To analyze miR-484 expression in DN and its association with clinicopathological parameters, as well as to elucidate its molecular regulation of Sodium-glucose cotransporter protein 2 (SGLT2), providing evidence for the early diagnosis of DN and miR-484/SGLT2-targeted therapies. METHOD: Clinical data were collected from healthy controls and T2DM patients. Total RNA was extracted for real-time PCR analysis. ROC curves, Pearson correlation, and logistic regression evaluated their clinical value. High glucose (30 mM)-treated HK-2 cell models and transfections with miR-484 mimics/inhibitors assessed cell proliferation, oxidative stress (MDA/SOD), inflammation (TNF-α/IL-6/IL-1β) using cell counting kit-8 (CCK-8) and ELISA, and SGLT2 targeting via dual-luciferase assays. RESULTS: DN patients exhibited lower serum miR-484 levels compared to controls and T2DM, negatively correlating with HbA1c and ACR, and positively correlating with eGFR. miR-484 was an independent risk factor for DN demonstrating high diagnostic sensitivity. High glucose downregulated miR-484 in HK-2 cells, inducing proliferation inhibition, oxidative stress, and inflammation; all of which were reversed by miR-484 mimics. Dual-luciferase assays confirmed that miR-484 directly targets the 3'UTR of SGLT2 to suppress its expression. CONCLUSION: The miR-484/SGLT2 axis is key to DN pathogenesis. miR-484 serum levels reflect DN severity and serve as a potential biomarker. Targeting SGLT2 via miR-484 offers new therapeutic strategies for DN by mitigating glucose reabsorption, oxidative stress, and inflammation.