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      Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy.

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          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.

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          Author and article information

          Journal
          Diabetes
          Diabetes
          1939-327X
          0012-1797
          Aug 2015
          : 64
          : 8
          Affiliations
          [1 ] Department of Nephrology, Kyoto University, Kyoto, Japan mtake@kuhp.kyoto-u.ac.jp abeabe@clin.med.tokushima-u.ac.jp.
          [2 ] Department of Nephrology, Kyoto University, Kyoto, Japan.
          [3 ] Department of Nephrology, Tokushima University, Tokushima, Japan mtake@kuhp.kyoto-u.ac.jp abeabe@clin.med.tokushima-u.ac.jp.
          [4 ] Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
          [5 ] Department of Nephrology, Tokushima University, Tokushima, Japan.
          [6 ] Chugai Research Institute for Medical Science, Inc., Shizuoka, Japan.
          [7 ] Kobe City Medical Center General Hospital, Kyoto, Japan.
          [8 ] National Center for Geriatrics and Gerontology, Aichi, Japan.
          Article
          db14-0893
          10.2337/db14-0893
          25995358
          © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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