Participation of bone morphogenetic protein (BMP)-6 and osteopontin in cisplatin (CDDP)-induced rat renal fibrosis

摘要

? 2014 Elsevier GmbH. ? 2014 Elsevier GmbH. The significance of bone morphogenetic protein (BMP)-6 and osteopontin (OPN) in renal fibrosis is poorly understood. We investigated the expression of BMP-6 and OPN in cisplatin (CDDP; 6. mg/kg, once, i.p.)-induced renal fibrosis in F344 rats, and their effects on kidney fibroblast (NRK-49F), mesenchymal pericyte (MT-9) and renal epithelial cell (NRK-52E) lines. Histopathologically, the CDDP injection showed desquamation of renal tubular epithelial cells at the cortico-medullary junction on days 1-3 that followed insufficient regeneration on days 5-9 and progressive interstitial fibrosis by day 35. In addition to TGF-β1 (the most powerful fibrogenic factor), increase in mRNAs of BMP-6 and OPN was seen consistently after the injection. Immunohistochemically, BMP-6 was expressed both in the damaged renal epithelial cells and spindle-shaped myofibroblasts (expressing α-smooth muscle action [α-SMA]) in the fibrotic areas; OPN expression was seen exclusively in the injured renal epithelial cells. Treatment of BMP-6 or OPN increased α-SMA mRNA in MT-9 cells, similar to effects of TGF-β1 on MT-9 and NRK-49F cells. Interestingly, TGF-β1 addition increased BMP-6 and OPN mRNAs in NRK-52E cells. Collectively, it was found that BMP-6 and OPN considerably participate in progressive renal fibrosis through development of myofibroblasts, in relation with TGF-β1. The significance of bone morphogenetic protein (BMP)-6 and osteopontin (OPN) in renal fibrosis is poorly understood. We investigated the expression of BMP-6 and OPN in cisplatin (CDDP; 6. mg/kg, once, i.p.)-induced renal fibrosis in F344 rats, and their effects on kidney fibroblast (NRK-49F), mesenchymal pericyte (MT-9) and renal epithelial cell (NRK-52E) lines. Histopathologically, the CDDP injection showed desquamation of renal tubular epithelial cells at the cortico-medullary junction on days 1-3 that followed insufficient regeneration on days 5-9 and progressive interstitial fibrosis by day 35. In addition to TGF-β1 (the most powerful fibrogenic factor), increase in mRNAs of BMP-6 and OPN was seen consistently after the injection. Immunohistochemically, BMP-6 was expressed both in the damaged renal epithelial cells and spindle-shaped myofibroblasts (expressing α-smooth muscle action [α-SMA]) in the fibrotic areas; OPN expression was seen exclusively in the injured renal epithelial cells. Treatment of BMP-6 or OPN increased α-SMA mRNA in MT-9 cells, similar to effects of TGF-β1 on MT-9 and NRK-49F cells. Interestingly, TGF-β1 addition increased BMP-6 and OPN mRNAs in NRK-52E cells. Collectively, it was found that BMP-6 and OPN considerably participate in progressive renal fibrosis through development of myofibroblasts, in relation with TGF-β1.