Wang Fei, Gong Zhe, Yang Nianjia, Zhou Gang, Jia Mengxue, Liu Wenjin, Zheng Huaqing, Bi Guangyu, Feng Ye
Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, People's Republic of China.
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States.
Am J Physiol Renal Physiol. 2025 Jul 1;329(1):F71-F86. doi: 10.1152/ajprenal.00346.2024. Epub 2025 May 27.
Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related protein 1 (CTRP1) plays a potential role in fibrosis and inflammation in other tissues, we investigated the role of CTRP1 in patients and mice with CKD. Here CTRP1 expression was increased in plasma and decreased in the kidneys of patients with CKD. Upregulation of renal CTRP1 with adeno-associated-CTRP1 was associated with decreased renal fibrosis, inflammation, macrophage accumulation, and activation in mice models. Mechanistically, CTRP1 abolished the expression of transforming growth factor beta 1 (TGFβ1)-induced macrophage M2-associated genes and the transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). In addition, upregulation of CTRP1 could partly downregulate lipopolysaccharide (LPS)-stimulated expression of proinflammatory genes in vitro. Conditioned media from TGFβ1-CTRP1-pretreated macrophages could less efficiently stimulate fibroblast activation compared with those from TGFβ1-pretreated macrophages. Thus, our study reveals local CTRP1 as a potential regulator of chronic inflammation and kidney fibrosis through regulating macrophage activation. Taken together, these findings support renal CTRP1 as a novel therapeutic target for CKD. Augmenting renal CTRP1 expression mitigates chronic inflammation and fibrosis by inhibiting pathological macrophage activation. These findings offer a novel mechanism of kidney inflammation and fibrosis. CTRP1 can be considered as a predictive marker and/or therapeutic target for patients with CKD.
慢性肾脏病（CKD）以持续炎症和进行性肾纤维化为特征，由于对其发病机制的认识不完整，仍然是一个重大的治疗挑战。由于C1q/TNF相关蛋白1（CTRP1）在其他组织的纤维化和炎症中发挥潜在作用，我们研究了CTRP1在CKD患者和小鼠中的作用。在此，CKD患者血浆中CTRP1表达增加，而肾脏中CTRP1表达降低。在小鼠模型中，腺相关CTRP1上调肾脏CTRP1与肾纤维化、炎症、巨噬细胞积聚及激活的减少相关。机制上，CTRP1消除了转化生长因子β1（TGFβ1）诱导的巨噬细胞M2相关基因以及转录调节因子Yes相关蛋白（YAP）/含PDZ结合基序的转录共激活因子（TAZ）的表达。此外，CTRP1上调可在体外部分下调脂多糖（LPS）刺激的促炎基因表达。与来自TGFβ1预处理巨噬细胞的条件培养基相比，来自TGFβ1-CTRP1预处理巨噬细胞的条件培养基刺激成纤维细胞激活的效率较低。因此，我们的研究揭示局部CTRP1通过调节巨噬细胞激活作为慢性炎症和肾纤维化的潜在调节因子。综上所述，这些发现支持肾脏CTRP1作为CKD的新型治疗靶点。增强肾脏CTRP1表达通过抑制病理性巨噬细胞激活减轻慢性炎症和纤维化。这些发现提供了肾脏炎症和纤维化的新机制。CTRP1可被视为CKD患者的预测标志物和/或治疗靶点。
