MicroRNA-155-5p Aggravates Adriamycin-Induced Focal Segmental Glomerulosclerosis through Targeting Nrf2

Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix and usually associated with nephrotic range proteinuria. FSGS is a huge burden to society; however, the mechanisms remain unclear and treatment is still lacking.

Adriamycin nephropathy was induced by Adriamycin injection and some mice were also injected with Anti-miR-155-5p LNA or YC-1 (a pharmacological inhibitor of HIF-1). At 6 weeks, the mice were sacrificed, and kidneys, blood and urine samples were collected for further analysis.

We demonstrated a significant increase of miR-155-5p in kidney tissues in Adriamycin-induced FSGS mouse models. We also found Adriamycin treatment led to the activation of HIF-1, and inhibition of HIF-1 using YC-1 partly prevented the induction of miR-155-5p. Functionally, anti-miR-155-5p attenuated kidney injury and delayed the progression of renal fibrosis. Further, anti-miR-155-5p also enhanced the expression of Nrf2 following Adriamycin treatment. Further, our luciferase microRNA target reporter assay verified Nrf2 as a direct target of miR-155-5p. Our further results indicated anti-miR-155-5p could suppress kidney oxidative stress and inflammation, also supporting Nrf2 was the direct target of miR-155-5p. Finally, we also found miR-155-5p did not increase in serum but significantly increased in urine, indicating urinary miR-155-5p may be useful for FSGS diagnosis.

This study identified a HIF-1/miR-155-5p/Nrf2 axis which can promote kidney oxidative stress and inflammation, finally aggravating kidney injury and accelerating the progression of renal fibrosis in FSGS. Moreover, the increase in urinary miR-155-5p may be useful for the diagnosis of FSGS.