title: Tubular Overexpression of Angiopoietin-1 Attenuates Renal Fibrosis.
abstract: Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietin-1 (Ang-1) is a secreted vascular growth factor that binds to the endothelial-specific Tie2 receptor. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury, but is dispensable in mature, quiescent vessels. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis. Previous studies have shown contradicting effects of overexpressing Ang-1 systemically on renal tubulointerstitial fibrosis when different engineered forms of Ang-1 are used. Here, we investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice. Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor β1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney. Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manson
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Heedoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Yeawon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Oncology Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Tuoen
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Qiusha
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Geminiani
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Austin
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Ying Maggie
authors.initials: YM
authors.lastname: Chen
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D042683:Angiopoietin-1 / Q000235:genetics*; D000818:Animals; D015415:Biomarkers; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D042683:Angiopoietin-1; D015415:Biomarkers; D024042:Collagen Type I; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse