Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Excessive TGF-beta 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-beta signaling on development of fibrosis, there is a lack of information on ablating TGF-beta signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-beta receptor knockout (T beta R parallel to(endo+/-)) mice to explore whether curtailed TGF-beta signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with T beta R parallel to(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, T beta R parallel to(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than T beta R parallel to(endo+/+) counterparts. In addition, partial deletion of T beta R parallel to in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-beta-induced canonical Smad2 signaling was reduced in T beta R parallel to(endo+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in T beta R parallel to(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in T beta R parallel to(+/-) ECs compared with T beta R parallel to(endo+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-beta signals favors Snnad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-beta signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.