Abstract: FR-OR109

Potential Therapeutic Targets for CKD by Comparative Analysis of Conserved Transcriptional Changes in Human and Mouse Kidney Fibrosis

Session Information

Category: Cell Biology

  • 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion

Authors

  • Shrestha, Rojesh, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Li, Szu-Yuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ko, Yi-An, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Bell, Thomas, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Donner, Aaron, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Brand, Emily, Ionis Pharmaceuticals, Carlsbad, California, United States
Background

Kidney fibrosis is the histological manifestation of chronic kidney disease (CKD). Kidney fibrosis is associated with global gene expression changes and while some of them might be causally related to disease development, others could be a consequence of the disease. While not all aspect of CKD is recapitulated in mouse models, changes that consistent in a different species could have a higher likelihood to be causal. Furthermore, genetic modification of mouse models can be used to understand causality.

Methods

We performed expression profiling for a large cohort (n=95) of human microdissected normal and CKD tubule samples. Using an adjusted linear regression model, we identified genes whose expression levels were significantly associated with phenotypic changes including GFR and tubulointerstitial fibrosis. By using RNA sequencing, we examined gene expression changes in four mouse fibrosis models; folate induced fibrosis (FA), unilateral ureteral obstruction (UUO), tubule specific Notch transgenic and podocyte specific risk allele APOL1 transgenic mice.

Results

We identified 761 conserved expression changes and 10 transcription factors between mouse and human kidney disease. Here, we focused on E74-like factor 4 (Elf4), which is mainly expressed in immune cells and fibroblasts. It is also an important transcription factor that mediates the effect of interferon response. Then, we developed and tested the effectiveness of antisense oligonucleotide (ASO) both in vitro and in vivo for Elf4 knock-down. ASO mediated knockdown of ELF4 in kidney prevented interstitial fibrosis in FA model. Mice injected with Elf4 ASO showed lower expression of fibrosis markers (vimentin, fibronectin, collagen) compared to control FA injected mice. In addition, Elf4 ASO mice also showed marked histological improvement in fibrosis.

Conclusion

Thus, comparative analysis of human and mouse kidney fibrosis have identified conserved genes and pathways in kidney fibrosis. These genes can serve as potential new biomarkers or therapeutic targets for kidney disease development.

Funding

  • NIDDK Support