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Kidney Week

Abstract: SA-PO971

Hypermethylation of MicroRNA-219 Is an Anti-Fibrotic Mechanism in Maladaptive Kidney Repair by Preserving ALDH1L2

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Wei, Qingqing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States

Epigenetic mechanisms, such as DNA methylation and microRNAs, regulate maladaptive kidney repair including renal fibrosis. By global sequencing, we identified the hypermethylation of microRNA-219-2 (mir-219) gene in unilateral ureter obstruction (UUO), 25 minutes of bilateral renal ischemia with 1 week reperfusion injury (I25/1wk), and 25 minutes of bilateral renal ischemia with 1month reperfusion injury (I25/1M). mir-219 hypermethylation was further confirmed by pyro-sequencing. The hypermethylation was associated with downregulation of mir-219. Functionally, mir-219 overexpression enhanced fibronectin expression in cultured renal cells during hypoxia or TGF-b1 treatment. In mice, inhibition of mir-219 with anti-mir-219 LNA suppressed fibronectin accumulation in UUO kidneys.


To understand how mir-219 regulates fibronectin expression, we performed RNA-induced silencing complex (RISC, the complex for microRNA to bind to its target) immunoprecipitation, followed by RNA-seq to identify the potential targets of mir-219.


The potential candidate targets of mir-219 were further narrowed down to 5 (CANX, ALDH1L2, SMG1, NR2C2, CRTC1) after examination of the existence of predicted mir-219 binding sites in the seed sequence of the mRNAs accumulated in RISC, the conservation of the predicted mir-219 binding sites between species (in both human and mouse), and the reported expression level of the proteins in kidney. By screening the protein expression of these candidates, we found that mir-219 overexpression significantly suppressed ALDH1L2 in renal cells. In mice, mir-219 inhibition preserved ALDH1L2 expression in ureter obstructed kidneys. The functional binding site of mir-219 in the 3’-UTR of ALDH1L2 mRNA was further confirmed by luciferase assay. When ALDH1L2 was knockdown by siRNAs, obviously more fibronectin was induced in renal cells during TGF-b1 treatment.


In conclusion, mir-219-2 gene hypermethylation may suppress mir-219 expression. The downregulation of mir-219 may reduce renal fibrosis by repressing ALDH1L2.


  • NIDDK Support