Selective estrogen receptor modulator attenuates albumin-induced apoptosis in renal proximal tubules through inhibition of mitochondrial stress

• Project/Area Number: 25461238
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: Fujimoto Sohachi 川崎医科大学, 医学部, 講師 (00319948)
• Co-Investigator(Kenkyū-buntansha): KASHIHARA Naoki 川崎医科大学, 医学部, 教授 (10233701) ; SATOH Minoru 川崎医科大学, 医学部, 准教授 (70449891)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 尿細管間質障害 / エストロゲン / ラロキシフェン / 蛋白尿 / ミトコンドリア / 酸化ストレス / 尿細管障害 / インフラマソーム / エストロゲン受容体刺激 / 脂肪酸結合アルブミン / 慢性腎臓病 / Raloxifene / 選択的エストロゲン受容体刺激薬 / アポトース

Outline of Final Research Achievements

Ｗe investigated whether the selective estrogen receptor modulator, raloxifene, could attenuate albumin-induced tubular injury through reducing mitochondrial oxidative stress.ICR-derived glomerulonephritis (ICGN) mice, a mouse strain with a hereditary nephrotic syndrome, underwent ovariectomy, and were treated with raloxifene (50μg/kg/day) for 6 weeks. Ovariectomy induced the apoptotic cell death in renal proximal cells (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining) and decreased cytochrome-c oxidase activity in mitochondria. Electron microscopy of the ovariectomized ICGN mice revealed morphologically abnormal mitochondria, and these changes were suppressed following treatment with raloxifene with upregulation of the mitochondrial thioredoxin system. Stimulation of estrogen receptor attenuated programmed cell death in renal proximal tubules induced by albumin-overload as a result of amelioration of mitochondrial dysfunction.

Research Products

• [Journal Article] Deficiency of endothelial nitric oxide signaling pathway exacerbates peritoneal fibrosis in mice (2015)
  • Author(s): Kadoya H, Satoh M, Nagasu H, Sasaki T, Kashihara N
  • Journal Title: Clin Exp Nephrol Volume: 19 Issue: 4 Pages: 567-575
  • DOI: 10.1007/s10157-014-1029-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination Irbesartan/Amlodipine versus Irbesartan/Cilnidipine for Attenuation of Albuminuria in Rats with Streptozotocin-Induced Diabetic Nephropathy. (2015)
  • Author(s): Satoh M, Nishi Y, Kadoya H, Itano S, Komai N, Sasaki T, Kashihara N
  • Journal Title: Pharm Anal Acta Volume: 6 Issue: 05 Pages: 369-369
  • DOI: 10.4172/2153-2435.1000369
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypertension promotes islet morphological changes with vascular injury on pre-diabetic status in SHRsp rats. (2014)
  • Author(s): Satoh M, Nagasu H, Haruna Y, Ihoriya C, Kadoya H, Sasaki T, Kashihara N.
  • Journal Title: Clin Exp Hypertens. Volume: 36 Issue: 3 Pages: 159-64
  • DOI: 10.3109/10641963.2013.804539
  • Peer Reviewed
• [Journal Article] Angiotensin II Regulates Islet Microcirculation and Insulin Secretion in Mice. (2014)
  • Author(s): Ihoriya C, Satoh M, Kuwabara A, Sasaki T, Kashihara N.
  • Journal Title: Microcirculation Volume: 21 Issue: 2 Pages: 112-23
  • DOI: 10.1111/micc.12094
  • Peer Reviewed
• [Presentation] インフラマソーム活性可とミトコンドリア障害 (2015)
  • Author(s): 長洲一
  • Organizer: Okayama Nephro-Talk
  • Place of Presentation: ホテルグランヴィア岡山,岡山市
  • Year and Date: 2015-08-04
  • Invited
• [Presentation] 酸化ストレスと腎障害 (2015)
  • Author(s): 佐藤稔、柏原直樹
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場､名古屋市
  • Year and Date: 2015-06-06
  • Invited
• [Remarks] 川崎医科大学 腎臓・高血圧内科学HP
  • URL: http://www.kawasaki-jinzo.net/greeting