Effect of forkhead box O1 in renal tubular epithelial cells on endotoxin-induced acute kidney injury

Mengxi Zhang, Wei Dong, Zhilian Li, Zhenmeng Xiao, Zhiyong Xie, Zhiming Ye, Shuangxin Liu, Ruizhao Li, Yuanhan Chen, Li Zhang, Mengjie Wang, Huaban Liang, Reshalaitigu Baihetiyaer, Rizvangul Apaer, Zheng Dong, Xinling Liang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F262-F272
JournalAmerican Journal of Physiology - Renal Physiology
Volume320
Issue number3
DOIs
StatePublished - 2021

Keywords

  • Acute kidney injury
  • Endotoxin
  • Forkhead box O1
  • Peroxisome proliferator-activated receptor-c coactivator 1a
  • Renal tubular epithelial cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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