MiR-590-3p Attenuates Acute Kidney Injury by Inhibiting Tumor Necrosis Factor Receptor-Associated Factor 6 in Septic Mice

Inflammation. 2019 Apr;42(2):637-649. doi: 10.1007/s10753-018-0921-5.

Abstract

Previous studies have been indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6)-induced inflammation leads to acute kidney injury (AKI). How microRNA (miR) contributes to this process is poorly defined. The aim of this study was to investigate whether miR-590-3p regulated lipopolysaccharide (LPS)-induced inflammatory response by inhibiting TRAF6. LPS-induced septic mice were treated with adenovirus expressing miR-590-3p (ad-miR-590-3p) via tail-vein injection. AKI was evaluated by examining serum cystatin C (CysC), serum β2-microglobulin (β2-MG), and blood urea nitrogen (BUN). The mRNA and protein levels were assayed by RT-qPCR and western blotting, respectively. The proliferation of podocytes was monitored using the MTT assay. Cell apoptosis was analyzed by flow cytometry. Survival outcomes in ad-miR-590-3p-transfected septic mice were markedly improved compared with mice with LPS-induced sepsis. Ad-miR-590-3p transfection significantly attenuated LPS-induced AKI, which was reflected by an improved glomerular filtration rate (GFR) as determined by measuring CysC, β2-MG, and BUN. Moreover, we observed that miR-590-3p was a novel regulator of TRAF6, binding to its 3'-untranslated regions (3'-UTRs). In vitro, a miR-590-3p gain-of-function mutation blocked LPS-induced podocyte growth inhibition and apoptosis, as well as overactivation of the inflammatory response. miR-590-3p has the ability to suppress LPS-induced AKI and podocyte apoptosis by targeting TRAF6. This might provide a novel strategy for the treatment of LPS-induced renal injuries.

Keywords: AKI; TRAF6; apoptosis; inflammatory response; miR-590-3p; sepsis.

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis
  • Inflammation / chemically induced
  • Lipopolysaccharides
  • Mice
  • MicroRNAs / genetics*
  • Podocytes / pathology
  • Sepsis / complications
  • Sepsis / pathology*
  • Survival Rate
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors*

Substances

  • Lipopolysaccharides
  • MIRN590 microRNA, mouse
  • MicroRNAs
  • TNF Receptor-Associated Factor 6