title: Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy.
abstract: Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. We have previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix (ECM) proteins in DN. However, little is known about the regulatory mechanisms that induce and activate Smad1. Here, bone morphogenetic protein 4 (Bmp4) was found to up-regulate the expression of Smad1 in mesangial cells and subsequently to phosphorylate Smad1 downstream of the advanced glycation end product-receptor for advanced glycation end product signaling pathway. Moreover, Bmp4 utilized Alk3 and affected the activation of Smad1 and Col4 expressions in mesangial cells. In the diabetic mouse, Bmp4 was remarkably activated in the glomeruli, and the mesangial area was expanded. To elucidate the direct function of Bmp4 action in the kidneys, we generated transgenic mice inducible for the expression of Bmp4. Tamoxifen treatment dramatically induced the expression of Bmp4, especially in the glomeruli of the mice. Notably, in the nondiabetic condition, the mice exhibited not only an expansion of the mesangial area and thickening of the basement membrane but also remarkable albuminuria, which are consistent with the distinct glomerular injuries in DN. ECM protein overexpression and activation of Smad1 in the glomeruli were also observed in the mice. The mesangial expansion in the mice was significantly correlated with albuminuria. Furthermore, the heterozygous Bmp4 knock-out mice inhibited the glomerular injuries compared with wild type mice in diabetic conditions. Here, we show that BMP4 may act as an upstream regulatory molecule for the process of ECM accumulation in DN and thereby reveals a new aspect of the molecular mechanisms involved in DN.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Health-Bioscience Institute, University of Tokushima, Tokushima, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.forename: Otoya
authors.initials: O
authors.lastname: Ueda
authors.forename: Chisato
authors.initials: C
authors.lastname: Goto
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Nakahara
authors.forename: Taichi
authors.initials: T
authors.lastname: Murakami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.forename: Seiji
authors.initials: S
authors.lastname: Kishi
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukushima
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D017127:Glycation End Products, Advanced; D051898:Smad1 Protein; C497401:Smad1 protein, mouse