title: BAMBI elimination enhances alternative TGF-β signaling and glomerular dysfunction in diabetic mice.
abstract: BMP, activin, membrane-bound inhibitor (BAMBI) acts as a pseudo-receptor for the transforming growth factor (TGF)-β type I receptor family and a negative modulator of TGF-β kinase signaling, and BAMBI(-/-) mice show mild endothelial dysfunction. Because diabetic glomerular disease is associated with TGF-β overexpression and microvascular alterations, we examined the effect of diabetes on glomerular BAMBI mRNA levels. In isolated glomeruli from biopsies of patients with diabetic nephropathy and in glomeruli from mice with type 2 diabetes, BAMBI was downregulated. We then examined the effects of BAMBI deletion on streptozotocin-induced diabetic glomerulopathy in mice. BAMBI(-/-) mice developed more albuminuria, with a widening of foot processes, than BAMBI(+/+) mice, along with increased activation of alternative TGF-β pathways such as extracellular signal-related kinase (ERK)1/2 and Smad1/5 in glomeruli and cortices of BAMBI(-/-) mice. Vegfr2 and Angpt1, genes controlling glomerular endothelial stability, were downmodulated in glomeruli from BAMBI(-/-) mice with diabetes. Incubation of glomeruli from nondiabetic BAMBI(+/+) or BAMBI(-/-) mice with TGF-β resulted in the downregulation of Vegfr2 and Angpt1, effects that were more pronounced in BAMBI(-/-) mice and were prevented by a MEK inhibitor. The downregulation of Vegfr2 in diabetes was localized to glomerular endothelial cells using a histone yellow reporter under the Vegfr2 promoter. Thus, BAMBI modulates the effects of diabetes on glomerular permselectivity in association with altered ERK1/2 and Smad1/5 signaling. Future therapeutic interventions with inhibitors of alternative TGF-β signaling may therefore be of interest in diabetic nephropathy.
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Ray C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Division of Nephrology and Institute of Physiology with Center of Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Lindenmeyer
authors.affiliation: Division of Nephrology and Institute of Physiology with Center of Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guillot
authors.affiliation: Tisch Cancer Institute and Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Baron
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Niansong
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Kyung
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY Renal Section, James J. Peter Veterans Administration Medical Center, Bronx, NY.
authors.forename: John C
authors.initials: JC
authors.lastname: He
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY detlef.schlondorff@mssm.edu.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlondorff
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D006801:Humans; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; C485672:Bambi protein, mouse; D008565:Membrane Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D016212:Transforming Growth Factor beta; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2