Reciprocal regulation between the molecular clock and kidney injury.
Reciprocal regulation between the molecular clock and kidney injury.
复制标题
DOI：
10.26508/lsa.202201886
复制
发表时间：
2023-10
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
这项工作描述了几种小鼠遗传模型中昼夜节律和肾损伤之间的串扰，确定了分子钟成分Cry对调节炎症、代谢和纤维化很重要。小管间质纤维化是导致慢性肾脏疾病的多种病因的共同病理底物。尽管昼夜节律的紊乱与肾脏疾病有关，但分子钟在纤维化发病机制中的作用仍不完全清楚。我们在损伤和纤维化的实验模型（单侧输尿管梗阻、叶酸和腺嘌呤肾毒性）中研究了分子钟与肾损害之间的关系，使用选择性缺乏时钟成分Bmal1、clock和Cry的转基因小鼠。我们发现分子时钟通路在受损的小管上皮细胞中富集，并伴有明显的代谢改变。在人小管上皮细胞中，TGFβ显著改变时钟组分的表达。尽管Clock在巨噬细胞介导的炎症反应中发挥作用，但Cry1和Cry2的联合缺失对中性粒细胞的募集至关重要，与纤维化恶化和代谢相关基因表达的重大转变相关。这些结果支持肾脏损伤破坏肾脏外周分子钟，进而促进与炎症和纤维化反应相关的代谢紊乱。
The work describes the crosstalk between the circadian rhythm and kidney damage in several mouse genetic models defining that the molecular clock component Cry is important to regulate inflammation, metabolism, and fibrosis. Tubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components Bmal1, Clock, and Cry. We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations. In human tubular epithelial cells, TGFβ significantly altered the expression of clock components. Although Clock played a role in the macrophage-mediated inflammatory response, the combined absence of Cry1 and Cry2 was critical for the recruitment of neutrophils, correlating with a worsening of fibrosis and with a major shift in the expression of metabolism-related genes. These results support that renal damage disrupts the kidney peripheral molecular clock, which in turn promotes metabolic derangement linked to inflammatory and fibrotic responses.
影响因子：
5.6
作者：
Zhou Y;Wu M;Xu L;Cheng J;Shen J;Yang T;Zhang L
通讯作者：
Zhang L