만성 요독 흰쥐에서 Hydroxychloroquine 투여에 의한 신 손상 억제 효과 (Effect of Hydroxychloroquine on the Progression of Renal Injury in Chronic Uremic Rats)

서지정보

· 발행기관 : 대한신장학회
· 수록지 정보 : Kidney Research and Clinical Practice / 20권 / 6호 / 964 ~ 974페이지
· 저자명 : 양지혜, 최영진, 진동찬, 양철우, 김용수, 방병기

초록

목 적 : Hydroxychloroquine(HCQ)은 일부 사이토카인의 억제와 항 섬유화 작용이 알려져있다. 본 연구에서는 만성 요독증을 유발한 흰쥐에서 HCQ가 만성 신부전증의 신 손상을 억제하는지 알아보고자 하였다. 방 법 : Sprague-Dawley 흰쥐의 신장을 5/6 절제하여 만성 요독증을 유발하고 정상 대조군(NC), 요독 흰쥐 대조군(UC), 요독 흰쥐에 HCQ 1일 10 mg/kg 투여 군(HCQ10) 및 20 mg/kg 투여 군(HCQ20)의 4군으로 나누어 12주간 혈압, 신 기능, 단백뇨 및 조직변화를 관찰하고,사구체에 침윤된 단핵구/대식세포는 면역조직화학법으로, MCP-1과 TGF-β1의 mRNA 발현은 역전사 효소 연쇄중합반응법으로 실험하였다. 결 과 : 혈압은 NC군에 비해 UC군에서 4주부터 12주까지 유의하게 높았으며, HCQ10군의혈압은 4주부터 12주까지, HCQ20군의 혈압은 4주에서 UC군에 비해 유의하게 낮았다. 혈청 요소 질소 및 혈청 크레아티닌은 NC군에 비해 UC군에서 4주부터 유의하게 높았으며, HCQ10및 HCQ20군은 UC군에 비해 8주 및 12주에 유의하게 낮았다. 혈청 크레아티닌 청소율은 NC군에 비해 UC군에서 4주부터 유의하게 낮았으며 HCQ10 및 HCQ20군은 UC군에 비해 8주 및12주에 유의하게 높았다. 24시간 단백뇨는 NC군에 비해 UC군에서 4주부터 유의하게 높았으며HCQ10군은 UC군에 비해 4주와 12주에서 낮았다. 사구체 경화는 NC군에서 거의 없었으며UC군은 4주부터 유의하게 증가하였고 HCQ10 및 HCQ20군은 UC군에 비해 8주 및 12주에 유의하게 감소하였다. 간질 섬유화는 NC군에 비해 UC군은 4주부터 유의하게 증가하였고HCQ10 및 HCQ20군은 4주에 UC군에 비해 유의하게 감소하였으나 8주 및 12주에는 유의한차이가 없었다. 사구체에 침윤된 단핵구/대식세포의 수는 NC군에 비해 UC군에서 4주부터 유의하게 높았으며 HCQ10 및 HCQ20군은 UC군에 비해 4주부터 12주까지 유의하게 낮아 NC군과 유사하였다. MCP-1 mRNA 발현은 NC군에 비해 UC군에서 4주 및 8주에 유의하게 높았으며HCQ10 및 HCQ20군은 UC군에 비해 4주부터 12주까지 낮은 경향을 보였으나 HCQ10군 8주에서만 통계적으로 유의하였다. TGF-β1 mRNA 발현은 NC군에 비해 UC군 4주 및 8주에 유의하게 높았으며 HCQ20군은 UC군에 비해 4주 및 8주에 유의하게 낮았다. 결 론 : 결론적으로 hydroxy chloroquine은 만성 요독 흰쥐에서 MCP-1과 TGF-β1의 발현을 억제하고, 사구체 경화와 간질 섬유화의 진행을 완화하여 신 기능의 악화와 단백뇨 증가를 일부 억제한다고 생각된다.

영어초록

Background : Hydroxychloroquine(HCQ) is known to inhibit proinflammatory cytokine production from stimulated mononuclear cells and to have anti-fibrotic effect. The aim of this study was to investigate if HCQ could ameliorate renal injury in chronic uremic rats. Methods : Using Sprague-Dawley rats, chronic uremia was induced by 5/6 nephrectomy. The rats were divided into 4 groups : normal control rats(NC), uremic control rats(UC) and uremic rats treated with HCQ 10 mg/kg/day(HCQ10) and 20 mg/kg/day (HCQ20). Blood pressure, renal functions, proteinuria and histological changes were followed up for 12 weeks. The glomerular monocyte/macrophage infiltration was evaluated by immunohistochemistry and mRNA expression of MCP-1 and TGF-`1 was analyzed by RT-PCR. Results : Blood pressure was higher in UC than that in NC from 4 to 12 weeks, and it was lower in HCQ10(from 4 to 12 weeks) and HCQ20(at 4 week) than that in UC. BUN and serum creatinine levels were significantly higher in UC than those in NC from 4 to 12 weeks, and those were significantly decreased in HCQ10 and HCQ20 compared to UC. Creatinine clearance was significantly lower in UC than that in NC from 4 to 12 weeks, and it was increased in HCQ10 and HCQ20 compared to UC. 24 hour proteinurea was significantly increased in UC from 4 to 12 weeks compared to NC, and it was decreased in HCQ10 at 4 and 12 weeks compared to UC. Glomerulosclerosis score was minimal in NC, but was significantly increased in UC from 4 to 12 weeks. It was significantly decreased in HCQ10 and HCQ20 at 8 and 12 weeks compared to UC. Interstitial fibrosis score was also significantly increased in UC from 4 to 12 weeks compared to NC, and it was significantly decreased in HCQ10 and HCQ20 only at 4 weeks compared to UC. The number of glomerular infiltrated monocyte/macrophage in UC was higher than that in NC from 4 weeks, and was peak at 8 weeks. But it was comparable among NC, HCQ10 and HCQ20. MCP-1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ10 at 8 weeks compared to UC. TGF-`1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ20 at 4 and 8 weeks compared to UC. Conclusions : Our results suggest that HCQ inhibits MCP-1 and TGF-`1 mRNA expression in renal cortical tissue and attenuates progression of glo-merulosclerosis and interstitial fibrosis in chronic uremic rats, which lead to amelioration of renal function and decrease in proteinuria in chronic uremic rats.

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