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

[摘要] 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 (T β RIIendo+/−) mice to explore whether curtailed TGF- β signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with T β RIIendo+/+ mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, T β RIIendo+/− mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than T β RIIendo+/+ counterparts. In addition, partial deletion of T β RII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF- β –induced canonical Smad2 signaling was reduced in T β RII+/− ECs; however, activin receptor-like kinase 1 (ALK1)–mediated Smad1/5 phosphorylation in T β RII+/− ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in T β RII+/− ECs compared with T β RII+/+ 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.

[学科分类] 泌尿医学