ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0201

Effect of Renal Tubular Epithelial Cell Forkhead Box O1 on Endotoxin-Induced AKI

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Liang, Xinling, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
  • Zhang, Mengxi, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
  • Dong, Wei, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
Background

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. Herein, we investigated the effect of FOXO1 on endotoxin-induced AKI and related mechanism.

Methods

In vivo, the mouse model of endotoxin-induced AKI was induced by intra-abdominal injection of LPS (10 mg/kg). The expression of FOXO1 and PGC1-α in mouse kidney were determined. Then we established a mouse model of renal overexpression of FOXO1 by in situ injection of FOXO1 adeno-related virus in renal cortex before intra-abdominal injection of LPS. In vitro, Human proximal tubular epithelial (HK-2) cells were stimulated with LPS (40μg/ml), then infected with FOXO1 overexpression adenoviruses. The cell viability was measured by MTT assay. The morphological changes of mitochondria were observed using mitotracker staining. Mito-SOX was used to detect the changes of mitochondrial superoxide content and the expression of FOXO1.

Results

In vivo, FOXO-1 downregulation in mice RTECs and mitochondrial damage was found in endotoxin-induced AKI. Overexpression of FOXO1 could improve renal function and reduce mitochondrial damage. PGC1-α was reduced in endotoxin-induced AKI and reversed by FOXO-1 overexpression. In vitro, exposure to LPS led to HK-2 cell viability decline, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of the FOXO1, PGC1-α and mitochondrial complex I/V . Moreover, over-expression of FOXO1 in HK-2 cells could increase HK-2 cell viability and PGC1-α expression, and alleviated altered mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA decreased PGC1-α expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed FOXO1 binding to the PGC1-α promoter in HK-2 cells.

Conclusion

In conclusion, downregulation of RTECs FOXO1 mediated endotoxin-induced AKI and mitochondrial damage. Over-expression of FOXO1 could improve renal injury and mitochondria dysfunction, at least partly via PGC1-α signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.

Funding

  • Government Support - Non-U.S.