Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China.
Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550025, China; School of Nursing, Guizhou Medical University, Guiyang, 550025, China.
Exp Cell Res. 2021 Nov 1;408(1):112856. doi: 10.1016/j.yexcr.2021.112856. Epub 2021 Sep 29.
Renal interstitial fibrosis (RIF) is the common irreversible pathway by which chronic kidney disease (CKD) progresses to the end stage. The transforming growth factor-β (TGF-β)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a common factor leading to inflammation-mediated RIF, but its downstream regulatory mechanism is still unclear. Bioinformatics analysis predicted that serum amyloid A protein 1 (SAA1) was one of the target genes for transcriptional activation of STAT3 signaling. As an acute phase reaction protein, SAA1 plays an important role in many inflammatory reactions, and research has suggested that SAA1 is significantly elevated in the serum of patients with CKD. In this research, multiple experiments were performed to investigate the role of SAA1 in the process of RIF. SAA1 was abnormally highly expressed in kidney tissue from individuals who underwent unilateral ureteral obstruction (UUO) and TGF-β-induced HK2 cells, and the abnormal expression was directly related to the transcriptional activation of STAT3. Additionally, SAA1 can directly target and bind valosin-containing protein (VCP)-interacting membrane selenoprotein (VIMP) to inhibit the function of the Derlin-1/VCP/VIMP complex, preventing the transportation and degradation of the misfolded protein, resulting in endoplasmic reticulum (ER) stress characterized by an increase in glucose-regulated protein 78 (GRP78) levels and ultimately promoting the occurrence and development of RIF.
肾间质纤维化（RIF）是慢性肾脏病（CKD）进展至终末期的常见不可逆途径。转化生长因子-β（TGF-β）/信号转导和转录激活因子 3（STAT3）信号通路是导致炎症介导的 RIF 的共同因素，但下游调控机制尚不清楚。生物信息学分析预测血清淀粉样蛋白 A 蛋白 1（SAA1）是 STAT3 信号转录激活的靶基因之一。作为急性反应蛋白，SAA1 在许多炎症反应中发挥重要作用，研究表明 SAA1 在 CKD 患者的血清中显著升高。在这项研究中，进行了多项实验来研究 SAA1 在 RIF 过程中的作用。在接受单侧输尿管梗阻（UUO）和 TGF-β诱导的 HK2 细胞的个体的肾脏组织中，SAA1 异常高表达，异常表达直接与 STAT3 的转录激活有关。此外，SAA1 可以直接靶向并结合含有 valosin 的蛋白（VCP）相互作用膜硒蛋白（VIMP），抑制 Derlin-1/VCP/VIMP 复合物的功能，防止错误折叠蛋白的运输和降解，导致内质网（ER）应激，特征是葡萄糖调节蛋白 78（GRP78）水平增加，最终促进 RIF 的发生和发展。
