Kidney Week

Abstract: TH-OR84

Contribution of Germline TET2 Variants to the Pathogenesis of Kidney Diseases through Impaired DNA Damage Repair and Activation of Cytosolic Nucleotide Sensors

Session Information

• Non-Cystic Genetic Kidney Diseases: Disease Genes, Modifiers, and Therapies
  October 24, 2024 | Location: Room 23, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Liang, Xiujie, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Xiujie Liang, MD, PhD

• Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Hongbo Liu, PhD

• Hu, Hailong, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Hailong Hu, PhD

• Zhou, Jianfu, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Jianfu Zhou, PhD

• Abedini, Amin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Amin Abedini, MD

• Sanchez Navarro, Andrea, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Andrea Sanchez Navarro, PhD

• Kloetzer, Konstantin A., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Konstantin A. Kloetzer, MD

• Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak, MD, PhD

Group or Team Name

• Susztak Lab.

Background

Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive.

Methods

To pinpoint the genes linked to kidney disease, we combined kidney function GWAS, human kidney expression quantitative trait analysis (eQTL), and methylation quantitative trait analysis (meQTL). To discover the variants that modify gene expression in kidney cells, we utilized single-cell chromatin accessibility (snATACseq) and (Crispr-based) genome editing. We created kidney-specific Tet2 knockout mice and manipulated gene expression in human kidney cells using CRISPR to study its role in kidney disease progression. We performed single-nucleus RNA sequencing studies in knock-out mice and RNA sequencing studies in TET2 knockdown tubule cells to delve into the role of Tet2.

Results

By integrating kidney function GWAS, human kidney eQTL and meQTL analyses, we identified TET2 as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influence TET2 expression in kidney proximal tubule cells. Experiments using kidney/tubule-specific Tet2 knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as chronic kidney disease and fibrosis, induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys from Tet2 knockout mice and TET2-knock-down tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably including INO80, another kidney function GWAS target gene itself.
Remarkably both TET2-null and INO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules or pharmacological inhibition of STING protected TET2 null mice from disease development.

Conclusion

Our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms.

Funding

• NIDDK Support