Anti-inflammatory effects of BMP7 on AGEs-induced tubular injury

Abstract

BACKGROUND: Formation and accumulation of advanced glycation end products (AGEs) are remarkably accelerated in the diabetic kidney. We recently demonstrated that AGEs stimulated various pro-inflammatory and pro-fibrotic responses in cultured human proximal tubular epithelial cells (PTEC). Bone morphogenetic protein (BMP) 7 has been reported to confer renoprotective effects in a variety of cell types and disease models. However, data is lacking in AGEs-induced renal tubular inflammation. Our present study explored the therapeutic potential of BMP7 on AGEs-induced tubular injury and its possible mechanisms. METHODS: Primary human PTEC were growth-arrested and exposed to glycated human serum albumin (AGE-HSA) with or without recombinant human BMP7 (rhBMP7). Pro-inflammatory chemokines and cytokines were detected at both gene and protein levels by real-time PCR and ELISA, respectively. Inhibitors of different signaling pathways were used (SB203580, PD98059 and PDTC for p38 MAPK, p44/42 MAPK and NF-κB respectively) to study the involvement of these pathways. RESULTS: AGE-HSA induced PTEC expression of pro-inflammatory factors through multiple pathways - IL8 through both p38 and p44/42 MAPK pathways, sICAM-1 through p44/42, and MCP1 through p38 MAPK. Although PDTC suppressed the mRNA and protein expression of IL-6 and TNF-α induced by AGE-HSA, AGE failed to stimulate NF-κB under these experimental conditions, indicating involvement of other pathways. rhBMP7 (5-200 ng/mL) dose-dependently attenuated AGE-HSA (100 ug/mL)-induced expression of sICAM-1, MCP1, IL8, TNF-α and IL6 at both mRNA and protein levels. Moreover, rhBMP7 suppressed phosphorylation of p38, p44/42 which was induced by AGE-HSA. CONCLUSIONS: Our in vitro results demonstrated that BMP7 can attenuate pro-inflammatory responses to AGE stimulation in PTEC via suppression of multiple signaling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule warrants further investigation.