MYO1C is a urinary extracellular vesicle biomarker and mediator of podocyte injury in diabetic nephropathy
Zihao Zhao, Qianqian Yan, Sijie Zhou, Fengxun Liu, Yong Liu, Jingjing Ren, Shaokang Pan, Zhenjie Liu, Dongwei Liu, Zhangsuo Liu, Jiayu Duan
Zihao Zhao, Qianqian Yan, Sijie Zhou, Fengxun Liu, Yong Liu, Jingjing Ren, Shaokang Pan, Zhenjie Liu, Dongwei Liu, Zhangsuo Liu, Jiayu Duan
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Research Article Inflammation Nephrology

MYO1C is a urinary extracellular vesicle biomarker and mediator of podocyte injury in diabetic nephropathy

Abstract

Type 2 diabetic nephropathy (T2DN) is a major complication of type 2 diabetes and a leading cause of chronic kidney disease. This study aimed to explore Myosin IC (MYO1C) as both a candidate biomarker and elucidate its role as a mechanistic mediator of podocyte injury in T2DN. Using urinary extracellular vesicle RNA biomarkers identified from a training and validation cohort of 33 type 2 diabetes and 40 patients with T2DN, we developed a machine learning diagnostic model for T2DN. The model achieved an AUC of 0.877 in validation and performed well in an independent test cohort with an AUC of 0.824. MYO1C was identified as the most influential feature in the final model. Mechanistic investigations in vitro and in vivo revealed that high glucose and high-fat conditions induced podocyte injury, inflammation, and apoptosis, with increased MYO1C expression. MYO1C knockdown in vitro and in vivo reduced podocyte damage and inflammatory responses. MYO1C overexpression enhanced p38, p-CREB, and TNF-α levels, while p38 inhibition mitigated these effects. These findings support MYO1C not only as a potential urinary biomarker for T2DN but also as a key pathogenic driver that promotes podocyte injury via p38 MAPK signaling.

Authors

Zihao Zhao, Qianqian Yan, Sijie Zhou, Fengxun Liu, Yong Liu, Jingjing Ren, Shaokang Pan, Zhenjie Liu, Dongwei Liu, Zhangsuo Liu, Jiayu Duan

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Figure 8

Podocyte-specific knockdown of Myo1c via AAV reduces renal injury in diabetic nephropathy mice.

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Podocyte-specific knockdown of Myo1c via AAV reduces renal injury in dia...
(A) Schematic representation of AAV-mediated podocyte-specific knockdown of Myo1c. Ten-week-old db/db mice were randomized and received a single i.v. injection of AAV containing a podocyte-specific promoter to knock down MYO1C (AAV-Myo1c) or an empty control vector (AAV-Control). (B) Changes in body weight and blood glucose levels at 0, 2, 4, 6, and 8 weeks post-AAV intervention. Data are presented as mean ± SEM (n = 10 per group). (C) Changes in UACR at 0, 2, 4, 6, and 8 weeks after AAV intervention. Data are presented as mean ± SEM (n = 10 per group).***P < 0.001. (D) At the 8-week endpoint, serum blood urea nitrogen (BUN), serum creatinine (Scr), and kidney-to-body weight ratio (KW/BW) were measured. Statistical comparisons were performed using 1-way ANOVA with Dunnett’s multiple-comparison test. (E) Representative IHC and immunofluorescence images of MYO1C staining in kidney tissues from each group. Scale bar: 20 μm. (F) Quantitative analysis of MYO1C IHC staining in glomerular regions. Asterisks indicate significant differences in staining intensity between the AAV-Myo1c group and the db/db group. Statistical comparisons were performed using 1-way ANOVA with Dunnett’s multiple-comparison test; ***P < 0.001. (G) Immunoblots of MYO1C and other key proteins in kidney tissues from each group. (H) Densitometric analysis of protein expression, presented as mean ± SEM (n = 6–10 per group). Statistical comparisons were performed using 1-way ANOVA with Dunnett’s multiple-comparison test. *P < 0.05, **P < 0.01.