382-P: Metallothionein-1/2 Alleviates Inflammation-Driven Progression of Diabetic Kidney

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Introduction and Objective: Diabetic nephropathy associated with type 2 diabetes (T2DN) involves inflammation as a key mechanism contributing to kidney dysfunction. However, no targeted agents to effectively control this process have been developed. This study aimed to investigate the role of metallothioneins-1/2 (MT-1/2) in the inflammation-driven progression of T2DN. Methods: MT-1/2 expression was assessed in kidney tissues from patients with T2DN and T2D using single-cell and spatial transcriptomic analyses. Cell line and animal experiments (e.g., high-fat diet, streptozotocin, and adenine-mixed diet models) were conducted to identify transcription factors, inflammatory mediators, and inducers associated with MT-1/2 expression. Results: Patients with high tubular MT-1/2 expression exhibited slower T2DN progression than those with low expression. Single-cell and spatial transcriptomic analyses revealed that MT-12 genes were upregulated in the proximal tubules of T2DN patients with stable kidney function. Ligand-receptor analysis identified transforming growth factor-β as an inducer of MT-1/2, while single-nucleus epigenomics integrated cell analysis confirmed nuclear receptor subfamily 1 group I member 3 as a key transcription factor. These findings were validated using human proximal tubular cell lines and mouse models. Sodium-glucose cotransporter 2 inhibitors enhanced tubular MT-1/2 expression, particularly under conditions of heightened inflammation in a mouse model. Conclusion: Elevated MT-1/2 expression in the proximal tubules provides protective effects in T2DN, especially when inflammation drives disease progression. While existing therapies primarily focus on reducing albuminuria, agents that induce MT-1/2 expression represent a novel therapeutic strategy by directly preserving tubular function. Disclosure J. Hwang: None. H. Yoon: None. M. Hong: None. B. Jang: None. D. Yun: None. C. Kang: None. S. Han: None.

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