title: Involvement of neutrophil gelatinase-associated lipocalin and osteopontin in renal tubular regeneration and interstitial fibrosis after cisplatin-induced renal failure.
abstract: The kidney has a capacity to recover from ischemic or toxic insults that result in cell death, and timely tissue repair of affected renal tubules may arrest progression of injury, leading to regression of injury and paving the way for recovery. To investigate the roles of neutrophil gelatinase-associated lipocalin (NGAL/lcn2) and osteopontin (OPN/spp1) during renal regeneration, the expression patterns of NGAL and OPN in the cisplatin-induced rat renal failure model were examined. NGAL expression was increased from day 1 after injection; it was seen mainly in the completely regenerating proximal tubules of the cortico-medullary junction on days 3-35; however, the expression was not seen in abnormally dilated or atrophied renal tubules surrounded by fibrotic lesions. On the other hand, OPN expression was increased from day 5 and the increased expression developed exclusively in the abnormal renal tubules. NGAL expression level well correlated with the proliferating activity in the regenerating renal epithelial cells, whereas OPN significantly correlated with the α-smooth muscle actin-positive myofibroblast appearance, expression of transforming growth factor (TGF)-β1, and the number of CD68-positive macrophages. Interestingly, rat renal epithelial cell line (NRK-52E) treated with TGF-β1 decreased NGAL expression, but increased OPN expression in a dose-dependent manner. Because increases of TGF-β1, myofibroblasts and macrophages contribute to progressive interstitial renal fibrosis, OPN may be involved in the pathogenesis of fibrosis; on the contrary, NGAL may play a role in tubular regeneration after injury. Expression analysis of NGAL and OPN would be useful to investigate the tubule damage in renal-toxicity.
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan; Laboratories of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano-shi, Osaka 598-8531, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kashiwagi
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tonomura
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kondo
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Masuno
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Fujisawa
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tsuchiya
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Mikinori
authors.initials: M
authors.lastname: Torii
authors.affiliation: Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Takasu
authors.affiliation: Laboratories of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano-shi, Osaka 598-8531, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Laboratories of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano-shi, Osaka 598-8531, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Laboratories of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano-shi, Osaka 598-8531, Japan. Electronic address: yamate@vet.osakafu-u.ac.jp.
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D005355:Fibrosis; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
chemical_list: D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D002945:Cisplatin
keywords: Cisplatin; Neutrophil gelatinase-associated lipocalin; Osteopontin; Renal failure