Abstract: FR-PO982
Fibrillin 1-Enriched Tissue Microenvironment Plays a Key Role in Mediating Vascular Rarefaction in CKD
Session Information
- Pathology and Lab Medicine: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Li, Li, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Fu, Haiyan, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Vascular rarefaction, characterized by reduced capillary density due to the loss of endothelial cells, is a common pathologic feature in a wide variety of CKD. However, how endothelial cells are lost in CKD remains elusive. In this study, we report that Fibrillin-1, an extracellular matrix glycoprotein, plays a critical role for mediating vascular rarefaction after kidney injury.
Methods
Unilateral ureteral obstruction (UUO) and unilateral ischemic-reperfusion (UIRI) were used as models of kidney fibrosis. Decellularized kidney tissue scaffold (KTS) was prepared. The differential expression of KTS proteins was analyzed by mass spectrometry proteomics. The role of fibrillin-1 in endothelial cell survival and proliferation was investigated in vitro. The expression of fibrillin-1 was knocked down by shRNA approach in vivo.
Results
Compared to sham controls, KTS from fibrotic kidney induced human umbilical vein endothelial cells (HUVEC) to undergo apoptosis, characterized by an increased expression of cleaved caspase-3, PARP-1, Fas and p53. KTS from fibrotic kidney also promoted endothelin-1 expression, and inhibited c-fos and cyclin D1 expression in response to mitogen stimulation. Mass spectrometry proteomics analyses identified 414 proteins that were differentially expressed in the KTS of control and fibrotic kidney. Fibrillin-1 was one of the most upregulated. In vitro, recombinant fibrillin-1 protein inhibited HUVEC proliferation and the expression of proliferation-related genes. Fibrillin-1 also induced the expression of Fas, FADD and p53 in HUVEC. Fibrillin-1 expression was markedly upregulated in multiple models of kidney fibrosis. Knockdown of renal fibrillin-1 expression by shRNA approach ameliorated kidney vascular rarefaction and reduced renal fibrosis after UIRI.
Conclusion
These studies demonstrate that fibrillin-1-enriched KTS is a hostile environment for endothelial cells, leading to vascular rarefaction in CKD. Targeted inhibition of fibrillin-1 could be a novel therapeutic strategy for protecting kidney integrity against vascular rarefaction in CKD.