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Kidney Week

Abstract: PO2497

Glutathione-Specific Gamma-Glutamylcyclotransferase 1 (Chac-1) Is a CKD Risk Gene

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Sullivan, Katie, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Guan, Yuting, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gu, Xiangchen, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Doke, Tomohito, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sheng, Xin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Pullen, Steven S., Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany
  • Kuo, Jay, Chinook Therapeutics Inc, Vancouver, British Columbia, Canada
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Genome-wide association studies (GWAS) have identified more than 300 loci where genetic variants associated with CKD development, however the causal variant, gene, cell type and the disease mechanism remain mostly unknown

Methods

We used expression of quantitative trait loci (eQTL) and computational integration coloc and transcriptome wide association analysis, to identify target genes for GWAS variants. We integrated human kidney single cell RNA and ATAC-seq to fine map likely causal variants. Using CRISPR technology we generated mice with genetic deletion of Chac1. Kidney injury was induced by folic acid injection, and uninephrectomy followed by streptozotocin injection. We have also analyzed primary tubule cells isolated from control (Chac1 +/+) and heterozygous (Chac1 +/-) mice.

Results

Integration of GWAS and human kidney eQTL dataset prioritized Chac1 as potential kidney disease risk gene. Lower CHAC1 level was protective. Single cell and immunofluorescence studies highlighted strong Chac1 expression in kidney tubules. Mice with a heterozygous deletion in C showed no phenotypic differences at baseline, however exhibited less fibrosis both in the folic acid and diabetic injury models compared to wild type animals. In vitro, Chac1 heterozygous cells showed improved survival following cisplatin treatment compared to wild type cells, but no difference in apoptosis or necroptosis. Chac1 +/- cells showed protection from cisplatin induced ferroptosis, including preserved cell viability, less lipid peroxidation and higher expression of ferroptosis inhibitors such as Aifm2 and Gpx4. Gluthathione levels were also higher in kidneys of Chac1 heterozygous mice when compared to controls potentially explaining their ferroptosis resistance.

Conclusion

Via the integration of kidney function GWAS and eQTL, mouse model and cell culture studies we identified Chac1 as a new kidney disease risk gene.

Funding

  • Other NIH Support