TY - JOUR
T1 - Effect of forkhead box O1 in renal tubular epithelial cells on endotoxin-induced acute kidney injury
AU - Zhang, Mengxi
AU - Dong, Wei
AU - Li, Zhilian
AU - Xiao, Zhenmeng
AU - Xie, Zhiyong
AU - Ye, Zhiming
AU - Liu, Shuangxin
AU - Li, Ruizhao
AU - Chen, Yuanhan
AU - Zhang, Li
AU - Wang, Mengjie
AU - Liang, Huaban
AU - Baihetiyaer, Reshalaitigu
AU - Apaer, Rizvangul
AU - Dong, Zheng
AU - Liang, Xinling
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China (Grant 81770667) and by Natural Science Foundation of Guangdong Province (Grant 2018A0303130284).
Publisher Copyright:
© 2021 American Physiological Society. All rights reserved.
PY - 2021
Y1 - 2021
N2 - Mitochondrial damage in renal tubular epithelial cells (RTECs) is a hallmark of endotoxin-induced acute kidney injury (AKI). Forkhead box O1 (FOXO1) is responsible for regulating mitochondrial function and is involved in several kidney diseases. Here, we investigated the effect of FOXO1 on endotoxin-induced AKI and the related mechanism. In vivo, FOXO1 downregulation in mouse RTECs and mitochondrial damage were found in endotoxin-induced AKI. Overexpression of FOXO1 by kidney focal adeno-associated virus (AAV) delivery improved renal function and reduced mitochondrial damage. Peroxisome proliferator-activated receptor-c coactivator 1-a (PGC1-a), a master regulator of mitochondrial biogenesis and function, was reduced in endotoxin- induced AKI, but the reduction was reversed by FOXO1 overexpression. In vitro, exposure to LPS led to a decline in HK-2 cell viability, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of FOXO1, PGC1-a, and mitochondrial complex I/V. Moreover, overexpression of FOXO1 in HK-2 cells increased HK-2 cell viability and PGC1-a expression, and it alleviated the mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA treatment decreased PGC1-a expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed that FOXO1 bound to the PGC1-a promoter in HK-2 cells. In conclusion, downregulation of FOXO1 in RTECs mediated endotoxin-induced AKI and mitochondrial damage. Overexpression of FOXO1 could improve renal injury and mitochondrial dysfunction, and this effect occurred at least in part as a result of PGC1-a signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.
AB - Mitochondrial damage in renal tubular epithelial cells (RTECs) is a hallmark of endotoxin-induced acute kidney injury (AKI). Forkhead box O1 (FOXO1) is responsible for regulating mitochondrial function and is involved in several kidney diseases. Here, we investigated the effect of FOXO1 on endotoxin-induced AKI and the related mechanism. In vivo, FOXO1 downregulation in mouse RTECs and mitochondrial damage were found in endotoxin-induced AKI. Overexpression of FOXO1 by kidney focal adeno-associated virus (AAV) delivery improved renal function and reduced mitochondrial damage. Peroxisome proliferator-activated receptor-c coactivator 1-a (PGC1-a), a master regulator of mitochondrial biogenesis and function, was reduced in endotoxin- induced AKI, but the reduction was reversed by FOXO1 overexpression. In vitro, exposure to LPS led to a decline in HK-2 cell viability, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of FOXO1, PGC1-a, and mitochondrial complex I/V. Moreover, overexpression of FOXO1 in HK-2 cells increased HK-2 cell viability and PGC1-a expression, and it alleviated the mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA treatment decreased PGC1-a expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed that FOXO1 bound to the PGC1-a promoter in HK-2 cells. In conclusion, downregulation of FOXO1 in RTECs mediated endotoxin-induced AKI and mitochondrial damage. Overexpression of FOXO1 could improve renal injury and mitochondrial dysfunction, and this effect occurred at least in part as a result of PGC1-a signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.
KW - Acute kidney injury
KW - Endotoxin
KW - Forkhead box O1
KW - Peroxisome proliferator-activated receptor-c coactivator 1a
KW - Renal tubular epithelial cells
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U2 - 10.1152/AJPRENAL.00289.2020
DO - 10.1152/AJPRENAL.00289.2020
M3 - Article
C2 - 33356954
AN - SCOPUS:85102222270
SN - 1931-857X
VL - 320
SP - F262-F272
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 3
ER -