title: Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy.
abstract: Diabetic nephropathy is the leading cause of end-stage renal disease. It is pathologically characterized by the accumulation of extracellular matrix in the mesangium, of which the main component is α1/α2 type IV collagen (Col4a1/a2). Recently, we identified Smad1 as a direct regulator of Col4a1/a2 under diabetic conditions in vitro. Here, we demonstrate that Smad1 plays a key role in diabetic nephropathy through bone morphogenetic protein 4 (BMP4) in vivo. Smad1-overexpressing mice (Smad1-Tg) were established, and diabetes was induced by streptozotocin. Nondiabetic Smad1-Tg did not exhibit histological changes in the kidney; however, the induction of diabetes resulted in an ∼1.5-fold greater mesangial expansion, consistent with an increase in glomerular phosphorylated Smad1. To address regulatory factors of Smad1, we determined that BMP4 and its receptor are increased in diabetic glomeruli and that diabetic Smad1-Tg and wild-type mice treated with a BMP4-neutralizing antibody exhibit decreased Smad1 phosphorylation and ∼40% less mesangial expansion than those treated with control IgG. Furthermore, heterozygous Smad1 knockout mice exhibit attenuated mesangial expansion in the diabetic condition. The data indicate that BMP4/Smad1 signaling is a critical cascade for the progression of mesangial expansion and that blocking this signal could be a novel therapeutic strategy for diabetic nephropathy.
authors.affiliation: Department of Nephrology, Kyoto University, Kyoto, Japan mtake@kuhp.kyoto-u.ac.jp abeabe@clin.med.tokushima-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Nephrology, Kyoto University, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Araki
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan mtake@kuhp.kyoto-u.ac.jp abeabe@clin.med.tokushima-u.ac.jp.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Otoya
authors.initials: O
authors.lastname: Ueda
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.affiliation: Chugai Research Institute for Medical Science, Inc., Shizuoka, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Goto
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kinosaki
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kishi
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Department of Nephrology, Kyoto University, Kyoto, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iehara
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukushima
authors.affiliation: Kobe City Medical Center General Hospital, Kyoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.affiliation: National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Nephrology, Tokushima University, Tokushima, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D055415:Bone Morphogenetic Protein 4; D051898:Smad1 Protein; C497401:Smad1 protein, mouse