Makoto Arita1,2, Eisei Sohara3, Naohiro Takahashi4, Hiroaki Kikuchi4, Ayaka Usui4, Taisuke Furusho4, Takuya Fujimaru4, Tamami Fujiki4, Tomoki Yanagi4, Yoshiaki Matsuura4, Kenichi Asano5, Kouhei Yamamoto6, Fumiaki Ando4, Koichiro Susa4, Shintaro Mandai4, Takayasu Mori4, Tatemitsu Rai4, Shinichi Uchida4. 1. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan. makoto.arita@riken.jp. 2. Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan. makoto.arita@riken.jp. 3. Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. esohara.kid@tmd.ac.jp. 4. Department of Nephrology, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. 5. Laboratory of Immune Regulation, The School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. 6. Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Abstract
BACKGROUND: Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. METHODS: To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. RESULTS: In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15-/- mice. Alox15-/- CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15-/- CKD mice. Mediator lipidomics revealed that Alox15-/- CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. CONCLUSION: Increased PGD2 in Alox15-/- CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.
BACKGROUND:Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. METHODS: To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. RESULTS: In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15-/- mice. Alox15-/- CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15-/- CKD mice. Mediator lipidomics revealed that Alox15-/- CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. CONCLUSION: Increased PGD2 in Alox15-/- CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.
Authors: Gerhard Krönke; Julia Katzenbeisser; Stefan Uderhardt; Mario M Zaiss; Carina Scholtysek; Gernot Schabbauer; Alexander Zarbock; Marije I Koenders; Roland Axmann; Jochen Zwerina; Hans W Baenckler; Wim van den Berg; Reinhard E Voll; Hartmut Kühn; Leo A B Joosten; Georg Schett Journal: J Immunol Date: 2009-08-12 Impact factor: 5.422
Authors: John R Montford; Colin Bauer; Jeremy Rahkola; Julie A Reisz; Deanna Floyd; Katharina Hopp; Danielle E Soranno; Jelena Klawitter; Mary C M Weiser-Evans; Raphael Nemenoff; Sarah Faubel; Seth B Furgeson Journal: Am J Physiol Renal Physiol Date: 2021-12-06
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