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 5

Characterization of renal and systemic changes in db/m and db/db+HFD mouse models of diabetic nephropathy.

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Characterization of renal and systemic changes in db/m and db/db+HFD mou...
(A) Body weight, blood glucose levels, and urinary albumin-to-creatinine ratio (UACR) measured at 8, 10, 14, and 18 weeks in db/m and db/db+HFD mice. (B) Postmortem analysis at 18 weeks, including kidney-to-body weight ratio (KW/BW), serum blood urea nitrogen (BUN), serum creatinine, triglycerides, and total cholesterol levels. Data are presented as mean ± SEM, with intergroup comparisons performed using the Mann-Whitney U test. *P < 0.05, **P < 0.01, **P < 0.001. (C) Macroscopic comparison of kidney size in db/m and db/db+HFD mice at 18 weeks, along with ELISA measurements of inflammatory cytokines in renal tissue homogenates. Each group: n = 8. **P < 0.01, ***P < 0.001. (D) Kidney pathology in db/m and db/db+HFD mice. Representative images of PAS and Masson’s trichrome staining (scale bar: 20 μm), and TEM images (scale bar: 2 μm) of glomerular. (E) Quantitative analyses of kidney histology, including mean glomerular tuft area, percentage of PAS-positive area in glomerular tufts, average glomerular basement membrane (GBM) thickness, and number of foot processes per μm of GBM. Each group: n = 5–6. Statistical comparisons were performed using 1-way ANOVA with Dunnett’s multiple-comparison test. (F) IHC MYO1C staining in kidney tissues from db/m and db/db+HFD mice. Glomerular regions (scale bar: 10 μm) and tubular interstitial regions (scale bar: 20 μm) are shown. (G) Densitometric analysis of MYO1C+ staining areas. “*” indicates significant differences in glomerular staining between db/db+HFD and db/m groups, while “#” indicates differences in tubular interstitial staining. Statistical comparisons were performed using the Mann-Whitney U test. *P < 0.05, **P < 0.01, ##P < 0.01. (H) Immunoblots of MYO1C protein expression in kidney tissues of mice at different ages. (I) Immunoblots of specified protein expression in kidney tissues of db/m and db/db+HFD mice at 18 weeks. (J) Myo1c, TNF-α, and Nphs2 mRNA levels in kidney tissues of mice, measured by qPCR. Data are presented as mean ± SEM, with intergroup comparisons performed using the Mann-Whitney U test. **P < 0.01, ***P < 0.001. Each group: n = 6–8.