Abstract：
OBJECTIVE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated.
METHODS: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II.
RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin.
CONCLUSIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.
METHODS: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II.
RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin.
CONCLUSIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.
摘要：
目的：激活肾素-血管紧张素系统，作为高血压和慢性肾脏疾病（CKD）的标志，是导致肾小管间质纤维化进展的关键病理生理因素。LIM和衰老细胞抗原样结构域蛋白1（LIMS1）通过与其他蛋白质形成复合物在控制细胞行为中起重要作用。这里,研究了LIMS1在血管紧张素II（AngII）诱导的高血压和肾小管间质纤维化中的功能和调节。
方法:用AngII处理C57BL/6小鼠以诱导肾小管间质纤维化。使用缺氧诱导因子-1α（HIF-1α）肾小管特异性敲除小鼠或LIMS1敲除AAV来研究其对AngII诱导的肾间质纤维化的影响。体外，HIF-1α或LIMS1在HK2细胞暴露于AngII后被敲低或过表达。
结果：在患有高血压肾病的人肾和AngII诱导的高血压模型的鼠肾中观察到肾小管LIMS1的表达增加。LIMS1的肾小管特异性敲除改善了AngII诱导的小鼠肾小管间质纤维化。此外，我们证明LIMS1在肾小管细胞中受HIF-1α转录调节,而肾小管HIF-1α敲除可改善LIMS1介导的肾小管间质纤维化.此外,LIMS1通过与波形蛋白相互作用促进AngII诱导的肾小管间质纤维化。
结论：我们得出结论，HIF-1α转录调节的LIMS1通过与波形蛋白相互作用在AngII诱导的肾小管间质纤维化中起核心作用。我们的发现代表了对AngII诱导的肾小管间质纤维化机制的新见解，并为CKD的进展提供了新的治疗靶标。
方法:用AngII处理C57BL/6小鼠以诱导肾小管间质纤维化。使用缺氧诱导因子-1α（HIF-1α）肾小管特异性敲除小鼠或LIMS1敲除AAV来研究其对AngII诱导的肾间质纤维化的影响。体外，HIF-1α或LIMS1在HK2细胞暴露于AngII后被敲低或过表达。
结果：在患有高血压肾病的人肾和AngII诱导的高血压模型的鼠肾中观察到肾小管LIMS1的表达增加。LIMS1的肾小管特异性敲除改善了AngII诱导的小鼠肾小管间质纤维化。此外，我们证明LIMS1在肾小管细胞中受HIF-1α转录调节,而肾小管HIF-1α敲除可改善LIMS1介导的肾小管间质纤维化.此外,LIMS1通过与波形蛋白相互作用促进AngII诱导的肾小管间质纤维化。
结论：我们得出结论，HIF-1α转录调节的LIMS1通过与波形蛋白相互作用在AngII诱导的肾小管间质纤维化中起核心作用。我们的发现代表了对AngII诱导的肾小管间质纤维化机制的新见解，并为CKD的进展提供了新的治疗靶标。
