@article{d24ccd7967254a92843102b99845777e,
title = "BAMBI elimination enhances alternative TGF-b 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.",
author = "Ying Fan and Xuezhu Li and Wenzhen Xiao and Jia Fu and Harris, {Ray C.} and Maja Lindenmeyer and Cohen, {Clemens D.} and Nicolas Guillot and Baron, {Margaret H.} and Niansong Wang and Kyung Lee and He, {John C.} and Detlef Schlondorff and Chuang, {Peter Y.}",
note = "Funding Information: Funding. M.H.B. is supported by National Institutes of Health grants DK-52191 and HL-62248. J.C.H. is supported by National Institutes of Health grants 1R01DK078897 and 1R01DK088541-01A1 and a Veterans Affairs Merit Review Award (1I01BX000345). P.Y.C. is supported by National Institutes of Health grant 1-R01-DK-098126-01A1. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Y.F., X.L., W.X., J.F., R.C.H., M.L., C.D.C., and N.G. performed the experiments. Y.F., R.C.H., M.L., C.D.C., N.G., K.L., D.S., and P.Y.C. analyzed the data. Y.F., K.L., D.S., and P.Y.C. wrote the manuscript. R.C.H. and M.H.B. provided the reagents. R.C.H., M.H.B., N.W., K.L., J.C.H., D.S., and P.Y.C. contributed to the discussion and reviewed the manuscript. J.C.H., D.S., and P.Y.C. designed the experiments. K.L., J.C.H., D.S., and P.Y.C. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: M.H.B. is supported by National Institutes of Health grants DK- 52191 and HL-62248. J.C.H. is supported by National Institutes of Health grants 1R01DK078897 and 1R01DK088541-01A1 and a Veterans Affairs Merit Review Award (1I01BX000345). P.Y.C. is supported by National Institutes of Health grant 1-R01-DK-098126-01A1. Publisher Copyright: {\textcopyright} 2015 by the American Diabetes Association.",
year = "2015",
month = jun,
doi = "10.2337/db14-1397",
language = "English",
volume = "64",
pages = "2220--2233",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "6",
}