Meclofenamic acid promotes cisplatin-induced acute kidney injury by inhibiting fat mass and obesity-associated protein-mediated m 6 A abrogation in RNA
The role of RNA methylation on the sixth N atom of adenylate (m A) in acute kidney injury (AKI) is unknown. FTO (fat mass and obesity-associated protein) reverses the m A modification in cisplatin-induced AKI. Here, we aimed to determine FTO's role in AKI. We induced AKI in c57BL/6 mice by intr...
Saved in:
Published in | The Journal of biological chemistry Vol. 294; no. 45; p. 16908 |
---|---|
Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
08.11.2019
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The role of RNA methylation on the sixth N atom of adenylate (m
A) in acute kidney injury (AKI) is unknown. FTO (fat mass and obesity-associated protein) reverses the m
A modification in cisplatin-induced AKI. Here, we aimed to determine FTO's role in AKI. We induced AKI in c57BL/6 mice by intraperitoneal cisplatin injection and treated the animal with vehicle or an FTO inhibitor meclofenamic acid (MA) for 3 days. Moreover, as an
model, human kidney proximal tubular cells (HK2 cells) were treated with cisplatin. We found that the cisplatin treatment reduces FTO expression and increases m
A levels
and
MA aggravated renal damage and increased apoptosis in cisplatin-treated kidneys, phenotypes that were correlated with reduced FTO expression and increased m
A levels. Moreover, MA promoted apoptosis in cisplatin-treated HK2 cells, which was correlated with the reduced FTO expression and increased m
A in HK2 cells. FTO protein overexpression reduced m
A levels and inhibited apoptosis in cisplatin-treated HK2 cells and also blocked the MA-induced increase in m
A levels and apoptosis rates. In agreement, overexpression of the m
A-generating methyltransferase-like 3 and 14 (METTL3 and METTL14) or siRNA-mediated FTO knockdown promoted apoptosis and enhanced m
A levels in cisplatin-treated HK2 cells. MA increased p53 mRNA and protein levels in AKI both
and
, and FTO overexpression reduced p53 expression and reversed the MA-induced p53 increase in AKI. In conclusion, reduced renal FTO expression in cisplatin-induced AKI increases RNA m
A levels and aggravates renal damages. |
---|---|
ISSN: | 1083-351X |