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タイトル: 腎移植慢性拒絶反応の病態と治療 : 非免疫学的因子, 免疫抑制剤による腎毒性
その他のタイトル: Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity
著者: 仲谷, 達也  KAKEN_name
浅井, 利大  KAKEN_name
著者名の別形: Nakatani, Tatsuya
Asai, Toshihiro
キーワード: Angiotensin-Converting Enzyme Inhibitors/therapeutic use
Animals
Benzazepines/therapeutic use
Cyclosporine/adverse effects
Immunosuppressive Agents/adverse effects
Kidney/drug effects
Kidney Transplantation
Magnesium/administration & dosage
Magnesium Deficiency/chemically induced/drug therapy
Male
Rats
Rats, Sprague-Dawley
Renin-Angiotensin System/physiology
発行日: Nov-2002
出版者: 泌尿器科紀要刊行会
誌名: 泌尿器科紀要
巻: 48
号: 11
開始ページ: 699
終了ページ: 705
抄録: SDラットに連日シクロスポリンA(CA)を皮下注してCA慢性腎毒性を促進させ, 単独投与(A群), 高Mg食併用(B群), アンギオテンシン変換酵素阻害剤併用(C群)で比較した.CAによる血中Mg濃度の進行的な低下は, Mg補給により改善された.creatinine clearanceはA群及びC群で有意に低下し, B群でも7日目に有意な低下を認めたが, その後A群, C群より有意に上昇し, 28日目には対照群と同レベルまで改善した.組織学的所見では, A群で28日目にヒト慢性CA腎毒性と同様の特徴的な組織像を認めたが, B群, C群では尿細管障害, 間質の線維化とも有意に抑制され, B群で顕著であった.又, monocyte/macrophageの遊走因子osteopontin mRNAは, A群で7日目から発現亢進し, その後進行的に上昇したが, B群ではこの上昇はほぼ完全に抑制され, C群では部分的な抑制であった.monocyte chemoattractant protein-1もA群で発現が亢進し, B群では有意に抑制されたが, C群には抑制効果を認めなかった
Immunosuppressant-induced nephrotoxicity contributes to kidney graft loss in the long-term as one of the non-immunologic factors. We previously reported that correction of cyclosporine A (CsA)-induced hypomagnesemia reduced chronic CsA nephrotoxicity. This study was conducted to elucidate the mechanism of the beneficial effects of magnesium (Mg) on CsA nephrotoxicity and examine the role of the renin-angiotensin system in this mechanism. We particularly focused on CsA-induced interstitial mononuclear cell infiltration. CsA (15 mg/kg/day, s.c.) was administered daily to rats maintained on low sodium diets for 7, 14 and 28 days. The inhibitory effects of Mg supplementation and those of angiotensin converting enzyme inhibitor (ACEI) were compared for renal function, renal histology, mononuclear cell infiltration and gene expression profile. CsA lowered creatinine clearance and developed characteristic tubulointerstitial fibrosis that were mostly evident at day 28. CsA-induced impairment of renal function was ameliorated by Mg supplementation but not by ACEI. Monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the duration of CsA administration. CsA markedly upregulated the expression of chemoattractant proteins, osteopontin and monocyte chemoattractant protein-1, concomitantly. These changes were markedly attenuated by Mg but only slightly by ACEI. CsA also promoted expression of fibrogenic molecules and extracellular matrices that were markedly attenuated by Mg but only slightly by ACEI. Similarly, CsA-induced tubulointestitial fibrosis was almost completely abolished by Mg supplementation but only partially attenuated by ACEI. These results suggested that Mg supplementation abolished CsA-induced precedent inflammatory cell influx possibly via inhibition of expression of chemoattractants and consequently suppressed tubulointerstitial fibrosis. In this beneficial mechanism, factors independent of renin-angiotensin system seem to be mainly involved.
URI: http://hdl.handle.net/2433/114858
PubMed ID: 12512145
出現コレクション:Vol.48 No.11

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