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논문분류	춘계학술대회 초록집
제목	Cyclo(His-Pro) prevents against oxidative stress-induced renal injury through activating Nrf2-mediated pathway.
저자	Yong Chul Kim, Kyu Hong Kim, Jong Joo Moon, Jin Seon Jeong, Ji Eun Kim, Sunwha Lee, Dong Ki Kim, Seung Hee Yang, Yon Su Kim
출판정보	2019; 2019(1):
키워드	Cyclo(His-Pro) \| apoptosis \| oxidative stress \| AKI \| CKD
초록	Apoptosis is a key feature of the pathogenicity associated with glomerular and tubulo-interstitial injury of acute kidney injury (AKI) and chronic kidney disease (CKD). Cyclo(His-Pro) (CHP) is an endogenous cyclic dipeptide that exerts cellular protective effects against oxidative damages. Here, we show that treatment with exogenous (recombinant) CHP prevented renal structural and functional injury triggered by experimental ischemia-reperfusion injury (IRI) model in mice as well as 5/6 nephrectomy (Nx) model in rat. In this study, to investigate the effect of CHP on AKI, we used IRI mice model and hypoxia-induced in vitro models with cultured human tubular epithelial cells (TECs). In addition, 5/6 nephrectomy rat model and TGFβ- and hydrogen peroxide (H2O2)-induced apoptosis models with cultured human podocytes were employed. Exogenous CHP pre-treatment prevented kidney function and accompanied by a significant reduction in ischemia-induced tubular injury, apoptosis, and inflammatory cell infiltration on renal IRI model. In vitro stimulation of TECs with hypoxia, CHP-mediated renal protection was associated with reduced IL-11, IL-18, reactive oxygen species (ROS) and the proportion of dead cells. Compared with control-treated 5/6 Nx rat, CHP-treated 5/6 Nx rat also restored kidney function and decreased proteinuria and pathologically decreased glomerulosclerosis, tubule-interstitial fibrosis in the remnant kidney of 5/6 nephrectomized rat. The administration of exogenous CHP significantly reduced not only ROS production via Nrf2-dependent pathway, but also the resultant apoptosis induced by H2O2 in cultured human podocytes. Microarray analysis highlights a cascade of specific gene expression patterns related to kidney injury, repair, and innate immunity. Notably, tubular epithelial cell and podocytes cell cycle arrest in G2/M mediates oxidative stress after injury. This study has uncovered a major protective role of CHP in renal IRI and 5/6 nephrectomy through TECs and podocytes regeneration that could be potentiated as a therapeutic strategy.
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