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Abstract: FR-PO324

The Role of FRAS1 Loss of Function in Rapid Renal Decline: Insights into the Downregulation of NPR1

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Author

  • Chen, Tiehua, University of Utah Health, Salt Lake City, Utah, United States
Background

Progressive renal decline, leading to end-stage kidney disease (ESKD), is a hallmark of diabetic nephropathy. Recently, we identified a rare missense variant (p.R2516C) in the FRAS1 gene, which plays a crucial role in maintaining glomerular integrity as an extracellular matrix protein, in a family affected by both diabetes and ESKD. This study aims to investigate the impact of the p.R2516C variant on FRAS1 function and its potential involvement in the progression of ESKD.

Methods

To examine the functional consequences of the variant, we employed CRISPR-Cas9 gene editing technology to generate three distinct HEK293 cell lines. These included two FRAS1 knock-in cell lines, one harboring the p.H2520H synonymous mutation as a control and the other carrying the missense p.R2516C variant. Additionally, a FRAS1 knock-out cell line was generated. RNA sequencing was conducted on these cell lines to identify genes with differential expression patterns.

Results

Through comprehensive analysis of the RNA sequencing data, we identified 119 significantly differentially expressed genes following FRAS1 perturbation, consisting of 57 upregulated and 62 downregulated genes. Further investigation focused on the top 10 upregulated and 10 downregulated genes, which revealed NPR1 (Natriuretic Peptide Receptor A/Guanylate Cyclase A) as an intriguing downregulated candidate gene whose downregulation in diabetic nephropathy and other forms of kidney disease is further supported by publicly available transcriptomic datasets.

Conclusion

The findings of this study highlight the positive regulatory relationship between FRAS1 and NPR1, while emphasizing the contribution of FRAS1 LOF to rapid renal decline. This study provides compelling evidence that the LOF of FRAS1 leads to the downregulation of NPR1, ultimately resulting in rapid renal decline. Given the crucial role of NPR1 in maintaining normal renal function, it represents a promising therapeutic target for individuals affected by FRAS1 LOF, diabetic kidney disease (DKD), or chronic kidney disease (CKD). Further investigations are warranted to explore the therapeutic implications of targeting NPR1 in these conditions.

Funding

  • NIDDK Support