Abstract: TH-OR17
LACTB Is a Kidney C Mitochondrial Metabolism
Session Information
- CKD Mechanisms: Prediction, Propagation, and Prevention
November 02, 2023 | Location: Room 119, Pennsylvania Convention Center
Abstract Time: 05:24 PM - 05:33 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Li, Shen, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Hu, Hailong, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background
Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function. However, the causal variants, genes, cell types, and disease mechanisms remain mostly unknown.
Methods
We integrated GWAS, human kidney expression of quantitative trait analysis using Bayesian colocations, transcriptome-wide association studies, and summary-based Mendelian randomization studies to identify likely causal genes for kidney function. We used single-cell RNA and ATACseq data to identify causal cell types. Finally, we generated mice with genetic deletion to study kidney disease mechanisms.
Results
We identified serine beta lactamase-like protein (LACTB) as a kidney disease risk gene. LACTB is expressed in kidney tubule cells. LACTB knockout mice were more susceptible to acute and chronic kidney injury induced by cisplatin and folic acid. LACTB knockout mice had lower cardiolipin levels and abnormal mitochondria morphology, causing elevated mitochondrial injury and activation of the cytosolic nucleotide sensing pathways (cGAS-STING) with an increment of inflammation. Cardiolipin is a crucial lipid for maintaining mitochondrial morphology and function. Additionally, we discovered that as a protease, LACTB cleaves PLA2G6, an enzyme involved in cardiolipin biosynthesis, generating a more active fragment that promotes cardiolipin production.
Conclusion
In summary, the integration of GWAS, epigenome analysis, mouse
models, and cultured cell systems has identified LACTB as a causal gene for kidney disease. LACTB plays a crucial role in regulating cardiolipin metabolism, mitochondrial function, and inflammation.
Funding
- NIDDK Support