BMP7 reduces tubular inflammation and oxidative stress in diabetic nephropathy

Abstract

BACKGROUND: 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. METHODS: Primary human proximal tubular epithelial cells (PTECs) were growth-arrested and exposed to glycated human serum albumin (AGEs) with or without BMP7. Nine-week-old db/db mice and their db/m littermates underwent uninephrectomy (Unx) or sham operation, and received BMP7 (300 µg/kg body weight) or vehicle intraperitoneally every other day for 8 weeks before sacrifice. RESULTS: In cultured human PTECs, exposure to AGEs induced overexpression of ICAM1, MCP1, IL-8 and IL-6, involving activation of p44/42 and p38 MAPK signaling. BMP7 dose-dependently attenuated AGE-induced upregulation 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, Unx db/db mice treated with BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3,549±816.2 µg/mg versus 8,612±2,037 µg/mg, p=0.036), BUN (33.26±1.09 mg/dL versus 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. CONCLUSIONS: BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple proinflammatory signaling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation. This study is supported by a General Research Fund of the Research Grants Council (Grant number: HKU7770/09M) of Hong Kong, and the National Basic Research Program of China 973 program no. 2012CB517600 (no. 2012CB517606). Funding: Government Support - Non-U.S.