Fibrillin-1-enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease

作者：Li, Li; Liao, Jinlin; Yuan, Qian; Hong, Xue; Li, Jing; Peng, Yiling; He, Meizhi; Zhu, Haili; Zhu, Mingsheng; Fan Fan Hou; Fu, Haiyan^*; Liu, Youhua^*

来源：Science Advances, 2021, 7(5): eabc7170.

DOI：10.1126/sciadv.abc7170

Endothelial cell injury leading to microvascular rarefaction is a characteristic feature of chronic kidney disease (CKD). However, the mechanism underlying endothelial cell dropout is poorly defined. Here, we show a central role of the extracellular microenvironment in controlling endothelial cell survival and proliferation in CKD. When cultured on a decellularized kidney tissue scaffold (KTS) from fibrotic kidney, endothelial cells increased the expression of proapoptotic proteins. Proteomics profiling identified fibrillin-1 (FBN1) as a key component of the fibrotic KTS, which was up-regulated in animal models and patients with CKD. FBN1 induced apoptosis of endothelial cells and inhibited their proliferation in vitro. RNA sequencing uncovered activated integrin alpha(v)beta(6)/transforming growth factor-beta signaling, and blocking this pathway abolished FBN1-triggered endothelial injury. In a mouse model of CKD, depletion of FBN1 ameliorated renal fibrotic lesions and mitigated vascular rarefaction. These studies illustrate that FBN1 plays a role in mediating vascular rarefaction by orchestrating a hostile microenvironment for endothelial cells.

• 单位
  南方医科大学