title: Protective effect of BMP-7 against aristolochic acid-induced renal tubular epithelial cell injury.
abstract: Aristolochic acid nephropathy (AAN) is regarded as a kind of rapidly progressive renal fibrosis caused by the ingestion of herbal remedies containing aristolochic acid (AA). Recent studies showed that bone morphogenetic protein-7 (BMP-7) exerts beneficial effects on acute and chronic kidney injuries induced by different pathological conditions. We examined whether BMP-7 protects human renal tubular epithelial cells (HK-2) against AA-induced injury in vitro. HK-2 cells were cultured with different concentrations of AA and BMP-7 for 48h. Cell viability was determined by Cell Counting Kit-8 assay and lactate dehydrogenase (LDH) release. The apoptosis rate and the activity of caspase 3 protease were also examined. Epithelial-to-mesenchymal transition (EMT) was determined by cell morphology, E-cadherin and α-smooth muscle actin (α-SMA) protein expression, and TGF-β(1) and collagen III secretion. Additionally, the effect of anti-TGF-β1 antibody on AA-induced EMT was assessed. Our results indicated that BMP-7 significantly increased cell proliferation, decreased apoptosis rate and attenuated activation of caspase-3, resulting in the protection of HK-2 cells from AA-induced cytotoxicity. In addition, studies on EMT revealed that BMP-7 could inhibit AA-induced myofibroblast phenotype and restored the epithelial morphology in a dose-dependent manner. It was partially through reducing the activation of a myofibroblast phenotype and production TGF-β1. Treatment with neutralizing anti-TGF-β1 antibody also blocked AA-induced EMT and collagen III secretion. Together, these observations strongly suggest that BMP-7 is a potent inhibitor of AA-induced renal tubular epithelial cell injury and might be a promising agent for aristolochic acid-induced kidney damage.
authors.affiliation: Institute of Nephrology of Chongqing, Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Zihua
authors.initials: Z
authors.lastname: Wang
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D034341:Aristolochic Acids / Q000633:toxicity*; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D015820:Cadherins / Q000032:analysis / Q000378:metabolism; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024061:Collagen Type III / Q000032:analysis / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D055419:Bone Morphogenetic Protein 7; D015820:Cadherins; D024061:Collagen Type III; D053773:Transforming Growth Factor beta1; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3