Curtailing Endothelial TGF-β Signaling Is Sufficient to... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

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

Xavier, Sandhya*,†; Vasko, Radovan*,†,‡; Matsumoto, Kei*,†; Zullo, Joseph A.*,†; Chen, Robert*,†; Maizel, Julien*,†; Chander, Praveen N.§; Goligorsky, Michael S.*,†

Departments of *Medicine, Pharmacology, Physiology, and

§Pathology, and

†Renal Research Institute, New York Medical College, Valhalla, New York; and

‡Department of Nephrology and Rheumatology, University Medical Center, Goettingen, Germany

Correspondence: Dr. Sandhya Xavier or Michael S. Goligorsky, Department of Medicine, Renal Research Institute, New York Medical College, 15 Dana Road, Valhalla, NY 10595. Email: [email protected] or [email protected]

Received October 30, 2013

Accepted June 25, 2014

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 (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.