Melatonin is a hormone produced by the pineal gland in the brain and it has been reported that melatonin plays an important role in cisplatin-induced renal damage. In this study, the underlying mechanisms of melatonin were evaluated in the cisplatin-treated mice and cells. Melatonin significantly ameliorated renal dysfunction, increased expression of tubular injury markers, caspase-3 activation, apoptotic cell death, protein expression of key components of the molecular machinery for necroptosis, activation of NF-κB, and mRNA expression of pro-inflammatory cytokines in cisplatin-treated mice and cells. Taken together, these data demonstrated that the protective effects of melatonin against cisplatin-induced renal dysfunction and structural damages through dual suppression of apoptosis and necroptosis.
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Melatonin Attenuates Cisplatin-Induced Nephrotoxicity through Dual Suppression of Apoptosis and Necroptosis
Kim, Jong Woo Department of Physiology
Graduate School Keimyung University
(Supervised by Professor Park, Jae Hyung)
Melatonin is a hormone produced by the pineal gland and is well
known to regulate the sleep-wake cycle. In addition, melatonin also has
beneficial effects such as anti-oxidant and anti-inflammatory properties
in various disease models. It has been reported that melatonin plays a
protective role against cisplatin-induced nephrotoxicity. However, the
mechanisms underlying the protective effect of melatonin on
cisplatin-induced kidney injury remains poorly understood. This study
showed that treatment of melatonin significantly ameliorated
cisplatin-induced kidney dysfunction and structural damages. Melatonin
inhibited cleaved caspase-3 and cleaved PARP-1 expressions in
cisplatin-treated mice. Necroptotic markers were markedly increased by
cisplatin treatment and these changes were also attenuated by melatonin.
In the cisplatin-treated mice, melatonin significantly inhibited expression
levels of phospho-NF-κB and pro-inflammatory cytokines. In renal
epithelial cell lines, melatonin also ameliorated cisplatin-induced cellular
apoptosis and necroptosis. These results suggest that melatonin protects
against cisplatin-induced renal dysfunction and structural damages
through dual suppression of apoptosis and necroptosis.
시스플라틴 유도 신독성에서 아포토시스와 네크롭토시스의 이중 억제에 의한 멜라토닌의 보호효과
김 종 우
계 명 대 학 교 대 학 원 의학과 생리학 전공 (지도교수 박 재 형)
멜라토닌은 뇌의 송과선에서 생산되는 호르몬으로 수면-각성 주기를 조
절하는 것으로 알려져 있다. 또한 멜라토닌은 다양한 질병 모델에서 항산화
및 항염증 작용과 같은 유익한 효과를 나타낸다. 멜라토닌은 시스플라틴에
의한 신독성으로부터 신장 조직을 보호하는 것으로 보고되었다. 하지만 그
기전은 아직까지 명확히 밝혀져 있지 않다. 본 연구에서는 시스플라틴을 투
여한 마우스 및 신장 세포주에서 멜라토닌의 효능을 확인하고 그 기전을
규명하였다. 동물실험에서 시스플라틴에 의한 혈액 요소질소 및 크레아티닌
의 혈청 수치 감소가 멜라토닌 처리에 의해 개선되었으며, 시스플라틴에 의
한 신장세포의 조직학적 변화도 멜라토닌 처리에 의해 개선되었다. 호중구
젤라티나제 결합 리포칼린과 신장 손상 분자-1과 같은 신장 관상세포의 손
상지표들의 발현이 시스플라틴에 의해 현저히 증가하였으며, 이는 멜라토닌
처리에 의해 억제되었다. 시스플라틴에 의해 신장 세포의 아포토시스와 네
크롭토시스 모두 현저히 증가하였으며, 아포토시스와 네크롭토시스 모두 멜
라토닌 처리에 의해 억제되었다. 시스플라틴에 의해 신장 조직의 염증성 사
이토카인들의 발현양도 현저히 증가하였으며, 멜라토닌 처리에 의해 유의하
게 감소되었다. 신장 세뇨관 상피 세포주를 이용한 실험에서도 시스플라틴
에 의한 아포토시스와 네크롭토시스 증가가 멜라토닌에 의해 모두 억제되
었다. 결론적으로 멜라토닌은 아포토시스와 네크롭토시스의 이중 억제를 통
하여 시스플라틴에 의한 신장의 기능이상과 구조적 손상을 예방하였다. 따
라서 멜라토닌은 시스플라틴에 의한 신독성을 예방할 수 있는 후보물질이
될 수 있다.