Role of bone morphogenetic protein-7 (BMP7) in diabetic tubulopathy

Abstract

BACKGROUND: The potential renoprotective role of BMP7 in diabetic nephropathy remains unknown. METHODS: Nine-week-old db/db mice and their db/m littermates underwent uninephrectomy (Unx) or sham operation, and received rh-BMP7 (300ug/kg body weight) or vehicle intraperitoneally every other day for 8 weeks before sacrifice. Primary human proximal tubular epithelial cells (PTECs) were growth-arrested and exposed to glycated human serum albumin (AGE-HSA) with or without rh-BMP7. RESULTS: Compared with vehicle control, Unx db/db mice treated with rh-BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (4,566±2,767 ug/mg vs. 7,338±5,748 ug/mg, p<0.05), serum BUN (33.3±3.46 mg/dL vs. 37.5±2.95 mg/dL, p<0.05), and renal cortical gene expression of IL-6, ICAM-1, CCL-2 and CCL-5. PAS staining of kidney tissue showed significantly less severe tubular damage and interstitial inflammatory cell infiltration in the BMP7-treated group. In cultured human PTECs, exposure to AGEHSA induced overexpression of sICAM-1, CCL-2, IL-8 and IL-6, involving activation of p44/42 and p38 MAPK signaling. BMP7 dose-dependently attenuated AGE-induced upregulation of sICAM-1, CCL-2, 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. CONCLUSIONS: Our results demonstrated for the first time that BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple signaling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation.