Kidney diseases (Basel, Switzerland) · 2026
Enhanced miR-214 in Vascular Endothelial Cells Retards Renal Inflammation and Glomerular Sclerosis in Five-Sixths Nephrectomy Mice.
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Tan Lingxiao, Fan Xinwen, Zhang Xiaolu, Li Shanshan, Yang Bingyu, Zhang Yue, Huang Songming, Jia Zhanjun, Gong Wei, Zhang Aihua, Li Shuzhen
Аннотация
INTRODUCTION: Vascular endothelial injury is a critical driver of renal dysfunction and glomerulosclerosis in chronic kidney disease (CKD). While endothelial damage-induced inflammation contributes to sclerosis, the underlying mechanisms remain unclear. Although miR-214 has been implicated in renal fibrosis, its role in vascular endothelial cells during glomerulosclerosis is undefined.
METHODS: In this study, we investigated miR-214 expression and function in renal endothelial cells using five-sixths nephrectomy (5/6Nx) mice, endothelial-specific and smooth muscle-specific miR-214 knockout models, CD31-enriched primary renal endothelial cells, and mouse aortic endothelial cells. Transcriptome analysis, bioinformatic prediction, luciferase reporter assays, cytokine profiling, and pro-inflammatory stimulation experiments were performed to evaluate the regulatory relationship between miR-214 and RELA-associated inflammatory signaling.
RESULTS: We observed significant miR-214 upregulation in renal endothelial cells of 5/6Nx mice. Endothelial-specific knockout of miR-214 aggravated glomerulosclerosis and endothelial dysfunction, whereas smooth muscle-specific knockout showed no significant effect. Transcriptome analysis revealed that miR-214 inhibition altered the NF-κB pathway, specifically upregulating RELA. Bioinformatic prediction and luciferase reporter assays supported a direct interaction between miR-214 and the RELA 3'-UTR in vitro. In CD31-enriched primary renal endothelial cells, modulation of miR-214 levels inversely regulated RELA expression. Cytokine profiling showed that miR-214 suppression enhanced pro-inflammatory secretion. Furthermore, pro-inflammatory stimulation experiments demonstrated that inhibition of miR-214 amplified RELA-associated endothelial inflammatory activation, while miR-214 overexpression attenuated it.
CONCLUSION: Collectively, these results suggest that endothelial miR-214 protects against glomerulosclerosis by restraining RELA-associated inflammatory signaling, highlighting endothelial-targeted modulation of miR-214 as a potential therapeutic strategy for CKD-related glomerular injury.
METHODS: In this study, we investigated miR-214 expression and function in renal endothelial cells using five-sixths nephrectomy (5/6Nx) mice, endothelial-specific and smooth muscle-specific miR-214 knockout models, CD31-enriched primary renal endothelial cells, and mouse aortic endothelial cells. Transcriptome analysis, bioinformatic prediction, luciferase reporter assays, cytokine profiling, and pro-inflammatory stimulation experiments were performed to evaluate the regulatory relationship between miR-214 and RELA-associated inflammatory signaling.
RESULTS: We observed significant miR-214 upregulation in renal endothelial cells of 5/6Nx mice. Endothelial-specific knockout of miR-214 aggravated glomerulosclerosis and endothelial dysfunction, whereas smooth muscle-specific knockout showed no significant effect. Transcriptome analysis revealed that miR-214 inhibition altered the NF-κB pathway, specifically upregulating RELA. Bioinformatic prediction and luciferase reporter assays supported a direct interaction between miR-214 and the RELA 3'-UTR in vitro. In CD31-enriched primary renal endothelial cells, modulation of miR-214 levels inversely regulated RELA expression. Cytokine profiling showed that miR-214 suppression enhanced pro-inflammatory secretion. Furthermore, pro-inflammatory stimulation experiments demonstrated that inhibition of miR-214 amplified RELA-associated endothelial inflammatory activation, while miR-214 overexpression attenuated it.
CONCLUSION: Collectively, these results suggest that endothelial miR-214 protects against glomerulosclerosis by restraining RELA-associated inflammatory signaling, highlighting endothelial-targeted modulation of miR-214 as a potential therapeutic strategy for CKD-related glomerular injury.