Activation of Bone Morphogenetic Protein 4 Signaling Leads to Glomerulosclerosis That Mimics Diabetic Nephropathy
| Autor: | Takeshi Matsubara, Kunihiko Nakahara, Otoya Ueda, Naoshi Fukushima, Hideharu Abe, Seiji Kishi, Kou-ichi Jishage, Toshio Doi, Tatsuya Tominaga, Toshikazu Araoka, Chisato Goto, Akira Mima, Taichi Murakami, Kojiro Nagai |
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| Rok vydání: | 2011 |
| Předmět: |
Glycation End Products
Advanced medicine.medical_specialty animal structures Bone Morphogenetic Protein 4 Biochemistry Smad1 Protein Diabetic nephropathy Extracellular matrix Mice chemistry.chemical_compound Glycation Internal medicine medicine Albuminuria Animals Diabetic Nephropathies Molecular Biology Mice Knockout Glomerulosclerosis Focal Segmental Glomerular basement membrane Glomerulosclerosis Molecular Bases of Disease Cell Biology medicine.disease Extracellular Matrix Up-Regulation Cell biology medicine.anatomical_structure Endocrinology chemistry Bone morphogenetic protein 4 Mesangial Cells embryonic structures Advanced glycation end-product Signal transduction |
| Zdroj: | Journal of Biological Chemistry. 286:20109-20116 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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