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Abstract: FR-OR41

Comparative Human and Mouse Kidney Transcriptomics Identify ELF4 as Potential Therapeutic Target

Session Information

Category: Pathology and Lab Medicine

  • 1600 Pathology and Lab Medicine

Authors

  • Hu, Hailong, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gu, Xiangchen, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Frederick, Julia, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Shrestha, Rojesh, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Mouse models provide an excellent tool to study kidney disease pathogenesis, but little is known how well mouse models recapitulate molecular changes of human CKD.

Methods

Here we created four different mouse kidney disease models a) unilateral ureteral obstruction, b) folic acid injection c) tubular specific overexpression of Notch1 and d) podocyte specific overexpression of risk variant APOL1. We performed detailed phenotyping and molecular profiling by RNA Sequencing of mouse models. We also generated RNA Sequencing for 95 human kidney samples. We used the CRISPR technology to generate mice with ELF4 deletion. We used antisense oligonucleotides for test the therapeutic potential of ELF4 inhibition.

Results

Using comparative bioinformatics approaches we identified 1256 genes and 47 transcription factors that were commonly regulated in all mouse CKD and in patients with CKD. In particular we identified ELF3 and ELF4 transcription factors as they were elevated both in all mouse models and patient samples. Mice with genetic deletion of Elf4 was healthy at baseline and showed protection from FA and cisplatin induced kidney fibrosis and disease. We found that ELF4 is mostly expressed in immune cells and influenced inflammation. Therapeutic inhibition of ELF4 was tested by injection of Elf4, which showed similar protection of kidney disease.

Conclusion

Comparative transcriptomics identified Elf4 as one of the key conserved transcription factor in human and mouse CKD. Genetic deletion or pharmacological inhibition of Elf4 protected mice from fibrosis.