Kidney Week

Abstract: TH-PO415

Integrated Analysis of Human and Mouse Kidney Transcriptomic Profiling Unveils the Role of ELF3 in Kidney Fibrosis

Session Information

• Glomerular Diseases: Inflammation and Fibrosis
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Hu, Hailong, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Hailong Hu,

• Gu, Xiangchen, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Xiangchen Gu,

• Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Jeffrey H. Miner,

• Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Katalin Susztak,

Background

Progressive and irreversible glomerulosclerosis and tubulointerstitial fibrosis is associated with loss of kidney function in patients with chronic kidney disease (CKD). Mice could be an excellent model organism to model to study glomerulosclerosis and fibrosis, however, individual mouse models does not fully recapitulate the complexity of the human disease.

Methods

Here we performed phenotypic characterization (glomerulosclerosis, fibrosis and kidney function) and RNA sequencing of five mouse kidney disease models including unilateral ureteral obstruction (UUO), folic acid nephropathy (FAN), tubule-specific overexpression of Notch1 and podocyte-specific expression of APOL1 risk variant, and the Col4a3 knockout, Alport syndrome model. RNA sequencing was also conducted to quantify unbiased gene expression in 95 human kidney samples, including controls and diabetic kidney disease. We used ELF3 chromatin immunoprecipitation and sequencing (ChIP-seq) data. Finally, we generated mice with tubule-specific genetic deletion of Elf3 and induced disease by folic acid injection.

Results

We identified 131 genes (including 6 transcription factors) that were commonly regulated in mouse kidney disease models and in CKD patients. Amongst the transcription factors, we identified ELF3 as a key transcriptional factor strongly associated with renal fibrosis in all mouse models and patient samples. ELF3 was mostly expressed in kidney tubular epithelial cells. Tubule-specific Elf3 knockout mice (KspCre Elf3^fl/fl) were phenotypically normal at baseline. KspCre Elf3^fl/fl mice showed less severe renal fibrosis compared with wild-type mice after folic acid injection. ChIP-seq data analysis indicated ELF3 binding to Stat3 and Twist1; genes associated with epithelial-to-mesenchymal transition and disease development.

Conclusion

These results indicate the key role of tubule-specific ELF3 in kidney fibrosis. Interfering ELF3 expression may provide a new therapeutic target for CKD treatment.