Abstract: FR-PO987
Mitochondrial Aldehyde Dehydrogenase rs671 Single Nucleotide Polymorphism Increases the Susceptibility of Kidney Injury in Adenine-Induced CKD Mice
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Hsieh, Tusty-Jiuan, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
- Wu, Miao-Yi, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
- Tsai, I-Hsuan, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
- Liu, Chia-Chu, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
- Tsai, Yi-chun, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
- Wu, Ming-Tsang, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwan
Background
In Taiwan, chronic kidney disease (CKD) and end stage kidney disease are major public health issues. Genetic factors increase the susceptibility and severity of kidney diseases. Genome-wide association studies have discovered hundreds of genomic loci associated with CKD. However, which genes are critical contributors to CKD remain unclear. ALDH2 is a mitochondrial enzyme and plays a central role in the liver to metabolize acetaldehyde produced from ethanol into acetate. In addition to liver, ALDH2 is also highly expressed in the kidney, especially in kidney tubular cells. ALDH2 gene has a variant ALDH2*2 allele (rs671) that appears to be the most prevalent in Han Chinese and Taiwanese as higher than 40% in population. Individuals who carry ALDH2*2 allele have lower ALDH2 enzyme activity. Thus far, limited studies investigate genetic polymorphisms of ALDH2 on chronic kidney disease. In this study, we investigated whether ALDH2*2 variants could increase susceptibility to kidney injury.
Methods
We conducted an animal model that male C57BL/6 mice and ALDH2*2 knock-in mice were treated with 100 mg/kg body weight/day of adenine in drinking water to induce early stage CKD. Transdermal GFR measuring system and urine albumin-creatinine ratio (uACR) were used to monitor kidney function. We applied Periodic Acid-Schiff (PAS) staining, Masson trichrome staining, TUNEL assay, MitoSOX staining, real-time PCR and Western blotting to observe kidney injury, fibrosis, apoptosis, mitochondrial ROS, mitochondrial DNA (mtDNA) copy number and related protein expression, respectively.
Results
We found that declined kidney function, tubular damage, tubulointerstitial fibrosis and apoptosis were enhanced in the ALDH2*2 knock-in mice, compared to the wild-type mice. The biomarkers of oxidative stress (MDA, 4-HNE), inflammasome (NLRP3) and fibrosis (Collagen I) were significantly elevated in the kidney of ALDH2*2 knock-in mice. We also observed increased mitochondrial ROS, decreased mtDNA copy number and differential expressed mitochondrial dynamic proteins (Pink1, Parkin, Mfn2, Opa1, Drp1, Fis1) in the kidney of ALDH2*2 knock-in mice.
Conclusion
Our findings suggest that the carrier of ALDH2*2 variant may be more susceptible to kidney injury due to mitochondrial dysfunction.
Funding
- Government Support – Non-U.S.