#1536 ITGA6 as a potential therapeutic target for inhibiting the progression of diabetic nephropathy

Abstract Background and Aims Diabetic nephropathy (DN), a leading cause of end-stage renal disease (ESRD), is driven by complex interactions between hyperglycemia, inflammation, oxidative stress, and extracellular matrix (ECM) remodeling in the kidney. Among the key molecules implicated in these processes, integrin alpha-6 (ITGA6) has emerged as a crucial mediator, making it a promising therapeutic target for slowing the progression of DN. In parallel, exosomes, which carry a distinct molecular cargo of proteins, nucleic acids, and lipids, have garnered increasing attention over the past decade as both biomarkers and potential therapeutic tools for the diagnosis and treatment of human diseases. The interplay between ITGA6 and exosome-mediated mechanisms may provide new insights into innovative strategies for managing DN. Method Summary-data-based Mendelian Randomization (SMR) was employed with external validation to investigate the causal relationship between ITGA6 and DN. The differential expression of ITGA6 in kidney samples from diabetic and non-diabetic populations was validated utilizing the GEO database (GSE142025). Experiments were conducted by using db/db mice as the DN mouse model and the littermate db/m mice as the control to collect urine and serum for extracellular vesicle gene sequencing at the onset, middle, and end points of the disease. After 12 weeks, all mice were sacrificed for analysis of renal morphology and expression of ITGA6. Results Through external validation, SMR suggests ITGA6 may have causality with DN (Fig. 1A and B). Additional findings from the GEO database indicate varying ITGA6 expression levels in kidney samples between diabetic and healthy individuals (Fig. 1C). Employing extracellular vesicle gene sequencing and Multidimensional Scaling, a notable decrease in ITGA6 levels was observed in the urine and serum of db/db mice compared to db/m mice (Fig. 2A, B, and C). This disparity was subsequently confirmed in mouse kidney samples, in which the expression of ITGA6 was decreased in diabetic mice (Fig. 2D). Conclusion These findings suggest that ITGA6 may be a potential target for treating DN and targeting ITGA6 could be a promising approach for DN therapy, warranting further clinical investigation. Funding Supported by Shenzhen Key Medical Discipline Construction Fund (grant no. SZXK009), Sanming Project of Medicine in Shenzhen (grant no. SZSM202211013), and The General Project of China Postdoctoral Science Foundation (grant no. 2024M762142).