Objective The purpose of this study was to explore the biological role of long noncoding RNA GAS5 in the progression of diabetic kidney disease and it's potential molecular mechanism.Methods Ten renal biopsies from the Affiliated Hospital of Southwest Medical University in 2023 were collected and stained with Masson and PAS, and the expression of LncRNA GAS5 in human Mesangial cells induced by high glucose (30mM) for 48 hours was detected by RT-qPCR. After overexpression or knockout of LncRNA GAS5 and miR-1228-3p, the proliferative activity of Mesangial cells, the expression of fibrosis-related proteins including fibronectin (FN), type IV collagen (Col-4) and transforming growth factor beta1 (TGF-β1) and the activation of PKC/MMP2 signal pathway were detected by RT-qPCR, cell proliferation assay, EdU assay and Western Blot.Results Masson's and PAS staining showed obvious mesangial hyperplasia, basement membrane glycogen increased, and fibrosis was obvious increased in the kidney tissue of patients with DKD；In DKD and Mesangial cells induced by high glucose, the expression of LncRNAGAS5 was down-regulated and fibrosis-related proteins were up-regulated. LncRNAGAS5 up-regulated PKC/MMP-2 signal pathway to inhibit Mesangial cells proliferation and fibrosis marker protein expression through synergistic up-regulation of miR-1228-3p expression.Conclusion LncRNA GAS5 inhibites Mesangial cells proliferation and fibrosis-related protein and expression by targeting miR-1228-3p/PKC/MMP2 axis. LncRNA GAS5/miR-1228-3p/PKC/MMP2 axis elucidates the pathological mechanism of diabetic kidney disease and provided a potential therapeutic target for the treatment of diabetic kidney disease