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

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.

Automated summary

This study demonstrates the crucial role of FBN1 in mediating vascular rarefaction in CKD by orchestrating a hostile microenvironment for endothelial cells. The upregulation of FBN1 in fibrotic kidney tissue was found in animal models and patients, leading to apoptosis and inhibition of proliferation in endothelial cells. RNA sequencing identified the activated integrin alpha(v)beta(6)/transforming growth factor-beta signaling as the key pathway in FBN1-induced endothelial injury, and blocking this pathway ameliorated renal fibrosis and vascular rarefaction in a mouse model of CKD.