title: BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy.
abstract: Bone morphogenetic protein 7 (BMP7) has been reported to confer renoprotective effects in acute and chronic kidney disease models, but its potential role in Type 2 diabetic nephropathy remains unknown. In cultured human proximal tubular epithelial cells (PTECs), exposure to advanced glycation end-products (AGEs) induced overexpression of intercellular adhesion molecule 1 (ICAM1), monocyte chemoattractant protein 1 (MCP1), interleukin 8 (IL-8) and interleukin 6 (IL-6), involving activation of p44/42 and p38 mitogen-activated protein kinase (MAPK) signalling. BMP7 dose-dependently attenuated AGE-induced up-regulation of ICAM1, MCP1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, uninephrectomized db/db mice treated with BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg compared with 8612±2037 μg/mg, P=0.036), blood urea nitrogen (33.26±1.09 mg/dl compared with 37.49±0.89 mg/dl, P=0.006), and renal cortical expression of ICAM1 and MCP1 at both gene and protein levels. In addition, BMP7-treated animals had significantly less severe tubular damage, interstitial inflammatory cell infiltration, renal cortical p38 and p44/42 phosphorylation and lipid peroxidation. Our results demonstrate that BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple inflammatory signalling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation.
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Rui Xi
authors.initials: RX
authors.lastname: Li
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Hao Jia
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Dickson W L
authors.initials: DW
authors.lastname: Wong
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Miao
authors.initials: M
authors.lastname: Lin
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.affiliation: *Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology* / Q000627:therapeutic use*; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases