title: Curtailing endothelial TGF-β signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD.
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.
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and sandhya_xavier@nymc.edu michael_goligorsky@nymc.edu.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and Department of Nephrology and Rheumatology, University Medical Center, Goettingen, Germany.
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasko
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and.
authors.forename: Kei
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Zullo
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and.
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.affiliation: Pathology, and.
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.affiliation: Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and sandhya_xavier@nymc.edu michael_goligorsky@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D000071063:Endoglin; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005492:Folic Acid; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D005492:Folic Acid; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: ALK1; Endoglin; Smad1/5; TGF-β receptor type II; microvasculature; renal fibrosis