<i>Glutathione-specific gamma–glutamylcyclotransferase 1</i> ( <i>CHAC1</i> ) increases kidney disease risk by modulating ferroptosis

Genome-wide association studies (GWASs) have identified more than 1000 loci where genetic variants correlate with kidney function. However, the specific genes, cell types, and mechanisms influenced by these genetic variants remain largely uncharted. Here, we identified <i>glutathione-specific gamma-glutamylcyclotransferase 1</i> (<i>CHAC1</i>) on chromosome 15 as affected by GWAS variants by analyzing human kidney gene expression and methylation information. Both <i>CHAC1</i> RNA and protein were expressed in the loop of Henle region in mouse and human kidneys, and <i>CHAC1</i> expression was higher in patients carrying disease risk variants. Using CRISPR technology, we created mice with a single functional copy of the <i>Chac1</i> gene (<i>Chac1^+/-</i>) that displayed no baseline phenotypic alterations in kidney structure or function. These mice demonstrated resilience to kidney disease in multiple models, including folic acid-induced nephropathy, adenine-induced chronic kidney disease, and uninephrectomy-streptozotocin-induced diabetic nephropathy. We further showed that CHAC1 plays a critical role in degrading the cellular antioxidant glutathione. Tubule cells isolated from <i>Chac1^+/-</i> mice showed increased glutathione, decreased lipid peroxidation, improved cell viability, and protection against ferroptosis. Expression of ferroptosis-associated genes was also lower in mice with only one copy of <i>Chac1</i>. Higher CHAC1 protein also correlated with ferroptosis-related protein abundance in kidney biopsies from patients with kidney disease. This study positions CHAC1 as an important mediator of kidney disease that influences glutathione concentrations and ferroptosis, suggesting potential avenues to explore for the treatment of kidney diseases.