NYMC Faculty Publications
Curtailing Endothelial TGF-Β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD
Author Type(s)
Faculty
DOI
10.1681/ASN.2013101137
Journal Title
Journal of the American Society of Nephrology
First Page
817
Last Page
29
Document Type
Article
Publication Date
4-1-2015
Abstract
Excessive TGF-β signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-β signaling on development of fibrosis, there is a lack of information on ablating TGF-β signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-β receptor knockout (TβRII(endo+/-)) mice to explore whether curtailed TGF-β signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TβRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TβRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TβRII(endo+/+) counterparts. In addition, partial deletion of TβRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-β-induced canonical Smad2 signaling was reduced in TβRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TβRII(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TβRII(+/-) ECs compared with TβRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-β signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-β signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.
Recommended Citation
Xavier, S., Vasko, R., Matsumoto, K., Zullo, J. A., Chen, R., Maizel, J., Chander, P. N., & Goligorsky, M. S. (2015). Curtailing Endothelial TGF-Β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD. Journal of the American Society of Nephrology, 26 (4), 817-29. https://doi.org/10.1681/ASN.2013101137