Targeting the miR ‐224‐5p/ PTEN pathway: A previously under‐characterized strategy to attenuate mesangial cell injury and predict prognosis in diabetic nephropathy

AIM: To ascertain the expression status and clinical performance of miR-224-5p in diabetic nephropathy (DN), alongside its molecular mechanism of regulating mesangial cell injury by targeting phosphatase and tensin homolog (PTEN). METHODS: Serum miR-224-5p and PTEN mRNA expression were detected in DN patients. Logistic regression was used to analyze independent risk indexes for the poor clinical outcomes in DN. Functional gain/loss and rescue experiments were performed. Target relationships were validated through dual-luciferase reporter assays. RESULTS: Serum miR-224-5p expression was significantly increased in DN patients (P < 0.001). It displayed moderate diagnostic performance for discriminating DN from T2DM (AUC = 0.796), and good predictive value (AUC = 0.833) for predicting 2-year adverse renal outcomes. MiR-224-5p level was significantly higher in patients with an unfavorable prognosis than those with a favorable prognosis (P < 0.001). Elevated miR-224-5p was identified as an independent risk factor for eGFR decline ≥30% (P = 0.001), but this finding was not applicable to end-stage renal disease (ESRD) due to insufficient case numbers for multivariate analysis. MiR-224-5p inhibition protected high-glucose mesangial cells via PTEN upregulation, an effect reversed by si-PTEN. CONCLUSION: Increased miR-224-5p expression may serve as a potential circulating biomarker for predicting eGFR decline in DN patients, but these findings are preliminary and require validation in independent cohorts using standardized exogenous spike-in normalization before clinical application. The independence of this association was only demonstrated for the eGFR decline ≥30% endpoint and not for ESRD due to limited statistical power.