title: Participation of bone morphogenetic protein (BMP)-6 and osteopontin in cisplatin (CDDP)-induced rat renal fibrosis.
abstract: 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; 6mg/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.
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yano
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors.forename: Hossain M
authors.initials: HM
authors.lastname: Golbar
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Safety Evaluation, Preclinical Assessment, Otsuka Pharmaceutical Factory, Tokushima 722-8601, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sawamoto
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano City, Osaka 598-8531, Japan. Electronic address: yamate@vet.osakafu-u.ac.jp.
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics* / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D005355:Fibrosis; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D053495:Osteopontin / Q000235:genetics* / Q000494:pharmacology; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C525818:Bmp6 protein, rat; D055418:Bone Morphogenetic Protein 6; D011994:Recombinant Proteins; C506897:Spp1 protein, rat; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D002945:Cisplatin
keywords: BMP-6; Cisplatin; Osteopontin; Renal fibrosis