BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy

Clin Sci (Lond). 2015 Feb;128(4):269-80. doi: 10.1042/CS20140401.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 7 / pharmacology*
  • Bone Morphogenetic Protein 7 / therapeutic use*
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / pathology*
  • Diabetic Nephropathies / physiopathology
  • Glycation End Products, Advanced / metabolism
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy
  • Inflammation / pathology*
  • Kidney Function Tests
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / pathology
  • Kidney Tubules, Proximal / physiopathology
  • Lipid Peroxidation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oxidative Stress / drug effects*
  • Phosphorylation / drug effects
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Bone Morphogenetic Protein 7
  • Glycation End Products, Advanced
  • Reactive Oxygen Species
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases