Abstract: SA-PO090
Cyclo(His-Pro) Prevents Against Oxidative Stress-Induced Renal Apoptosis and Fibrosis Through Activating the Nrf2-Mediated Pathway
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kim, Ji Eun, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Kim, Yong Chul, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Moon, Jong joo, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Jeong, Jinseon, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Lee, Sunhwa, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Kim, Dong Ki, Seoul National University Hospital, Seoul, Korea (the Republic of)
- Kim, Yon Su, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
- Yang, Seung Hee, Kidney Research Institute, Seoul National University, Seoul, Korea (the Republic of)
Background
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.
Methods
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.
Results
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.
Conclusion
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.