缺氧诱导的 HIF-1α 表达通过 EMT 和细胞焦亡促进神经源性膀胱纤维化。
Hypoxia-Induced HIF-1α Expression Promotes Neurogenic Bladder Fibrosis via EMT and Pyroptosis.
机构信息
Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
出版信息
Cells. 2022 Nov 29;11(23):3836. doi: 10.3390/cells11233836.
BACKGROUND
Neurogenic bladder (NB) patients exhibit varying degrees of bladder fibrosis, and the thickening and hardening of the bladder wall induced by fibrosis will further affect bladder function and cause renal failure. Our study aimed to investigate the mechanism of bladder fibrosis caused by a spinal cord injury (SCI).
METHODS
NB rat models were created by cutting the bilateral lumbar 6 (L6) and sacral 1 (S1) spinal nerves. RNA-seq, Western blotting, immunofluorescence, cell viability and ELISA were performed to assess the inflammation and fibrosis levels.
RESULTS
The rats showed bladder dysfunction, upper urinary tract damage and bladder fibrosis after SCI. RNA-seq results indicated that hypoxia, EMT and pyroptosis might be involved in bladder fibrosis induced by SCI. Subsequent Western blot, ELISA and cell viability assays and immunofluorescence of bladder tissue confirmed the RNA-seq findings. Hypoxic exposure increased the expression of HIF-1α and induced EMT and pyroptosis in bladder epithelial cells. Furthermore, HIF-1α knockdown rescued hypoxia-induced pyroptosis, EMT and fibrosis.
CONCLUSION
EMT and pyroptosis were involved in the development of SCI-induced bladder fibrosis via the HIF-1α pathway. Inhibition of the HIF-1α pathway may serve as a potential target to alleviate bladder fibrosis caused by SCI.
背景
神经源性膀胱（NB）患者表现出不同程度的膀胱纤维化，纤维化引起的膀胱壁增厚和变硬将进一步影响膀胱功能并导致肾衰竭。我们的研究旨在探讨脊髓损伤（SCI）引起的膀胱纤维化的机制。
方法
通过切断双侧腰 6（L6）和骶 1（S1）脊神经来建立 NB 大鼠模型。通过 RNA-seq、Western blot、免疫荧光、细胞活力和 ELISA 评估炎症和纤维化水平。
结果
SCI 后大鼠出现膀胱功能障碍、上尿路损伤和膀胱纤维化。RNA-seq 结果表明，缺氧、上皮间质转化（EMT）和细胞焦亡可能参与了 SCI 引起的膀胱纤维化。随后的 Western blot、ELISA 和细胞活力测定以及膀胱组织免疫荧光证实了 RNA-seq 的发现。缺氧暴露增加了 HIF-1α 的表达，并诱导膀胱上皮细胞发生 EMT 和细胞焦亡。此外，HIF-1α 敲低挽救了缺氧诱导的细胞焦亡、EMT 和纤维化。
结论
通过 HIF-1α 通路，EMT 和细胞焦亡参与了 SCI 诱导的膀胱纤维化的发展。抑制 HIF-1α 通路可能成为缓解 SCI 引起的膀胱纤维化的潜在靶点。
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