caa a22 4500 445882395 CHVBK 20180317145547.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10157-010-0373-1 doi (NATIONALLICENCE)springer-10.1007/s10157-010-0373-1 Aldosterone-induced kidney injury is mediated by NFκB activation [Elektronische Daten] [Seiichi Fukuda, Chihiro Horimai, Kaori Harada, Toshifumi Wakamatsu, Hiroshi Fukasawa, Susumu Muto, Akiko Itai, Matsuhiko Hayashi] Background: Aldosterone induces inflammation and fibrosis in the kidney, while nuclear factor κB (NFκB) plays key roles in inflammation mediated by various cytokines. Here, we determined the roles of NFκB activation in aldosterone-induced kidney injury. Methods: We used unilaterally nephrectomized rats with or without continuous aldosterone infusion and 0.9% saline as drinking water for 3weeks. IMD-1041, an IKKβ inhibitor, and spironolactone were orally administered to inhibit NFκB and mineralocorticoid receptor, respectively. Results: The aldosterone-infused rats exhibited severe kidney injury, hypertension, and increased expression of pro-inflammatory and fibrotic proteins, osteopontin, fibrinogen, collagen type I, and PAI-1. Western blotting confirmed NFκB activation by aldosterone by the increased amount of p65 in the nuclear fraction of the kidney, and oral IMD-1041 prevented the kidney injury and lessened the increase in pro-inflammatory and fibrotic proteins without significant changes in blood pressures. In addition, changes in angiotensin-converting enzyme 2 (ACE2), which has been found to act as a protective factor in various kidney injury models, were examined. Immunofluorescence studies revealed the presence of ACE2 in the brush-border membrane of the proximal convoluted tubules and markedly blunted ACE2 staining in aldosterone-infused rats. The decrease in amount of ACE2 protein was confirmed by Western blotting, and IMD-1041 also prevented the decrease in ACE2. The administration of spironolactone also abolished the effects of aldosterone. Conclusion: Our results suggest that aldosterone induces kidney injury via activation of NFκB and mineralocorticoid receptor, and that decreased ACE2 expression may play an important role in aldosterone-induced kidney injury. Japanese Society of Nephrology, 2010 Aldosterone nationallicence Cytokines nationallicence Inflammation nationallicence Progression of chronic renal failure nationallicence Fukuda Seiichi Department of Internal Medicine, International University of Health and Welfare, Mita Hospital, 108-8329, 1-4-3 Mita, Minato-ku, Japan aut Horimai Chihiro Apheresis and Dialysis Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut Harada Kaori Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut Wakamatsu Toshifumi Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut Fukasawa Hiroshi Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut Muto Susumu Institute of Medicinal Molecular Design Inc., Kadokawa Hongo Bldg. 4F, 5-24-5 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan aut Itai Akiko Institute of Medicinal Molecular Design Inc., Kadokawa Hongo Bldg. 4F, 5-24-5 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan aut Hayashi Matsuhiko Apheresis and Dialysis Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut Clinical and Experimental Nephrology Springer Japan 15/1(2011-02-01), 41-49 1342-1751 15:1<41 2011 15 10157 https://doi.org/10.1007/s10157-010-0373-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10157-010-0373-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fukuda Seiichi Department of Internal Medicine, International University of Health and Welfare, Mita Hospital, 108-8329, 1-4-3 Mita, Minato-ku, Japan aut NATIONALLICENCE 700 1- Horimai Chihiro Apheresis and Dialysis Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut NATIONALLICENCE 700 1- Harada Kaori Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut NATIONALLICENCE 700 1- Wakamatsu Toshifumi Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut NATIONALLICENCE 700 1- Fukasawa Hiroshi Institute of Medicinal Molecular Design Inc., 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut NATIONALLICENCE 700 1- Muto Susumu Institute of Medicinal Molecular Design Inc., Kadokawa Hongo Bldg. 4F, 5-24-5 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan aut NATIONALLICENCE 700 1- Itai Akiko Institute of Medicinal Molecular Design Inc., Kadokawa Hongo Bldg. 4F, 5-24-5 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan aut NATIONALLICENCE 700 1- Hayashi Matsuhiko Apheresis and Dialysis Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan aut NATIONALLICENCE 773 0- Clinical and Experimental Nephrology Springer Japan 15/1(2011-02-01), 41-49 1342-1751 15:1<41 2011 15 10157 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer