Abstract: FR-PO0173
Deficiency of ALDH2 Orchestrates Diabetic Kidney Disease Progression by Promoting 4-Hydroxynonenal-Mediated Carbonylation and Degradation of Peroxisome Proliferator-Activated Receptor α (PPARα)
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Li, Qiong, The Fifth Affiliated Hospital of Sun Yat-sen University, ZhuHai, GuangDong, China
- Cheng, Wang, The Fifth Affiliated Hospital of Sun Yat-sen University, ZhuHai, GuangDong, China
Background
Metabolic reprogramming in proximal tubular epithelial cells is a pivotal driver of tubulointerstitial fibrosis in diabetic kidney disease (DKD). ALDH2 is a mitochondrial enzyme detoxifying 4-hydroxynonenal (4-HNE), yet its precise role in DKD pathogenesis remains to be fully elucidated.
Methods
We performed proteomics and non-targeted metabolomics on renal biopsies from patients with DKD and db/db mice respectively. The clinical relevance of ALDH2 expression was validated in an independent DKD patient cohort. In vitro studies utilized high-glucose (HG)-stimulated HK-2 cells. Molecular interactions were characterized using Co-immunoprecipitation, cycloheximide chase experiments, and ubiquitination analysis. In vivo, the therapeutic efficacy of the ALDH2 activator, Alda-1, was evaluated in a high-fat diet/STZ-induced DKD mouse model.
Results
Multi-omics analysis revealed a profound suppression of fatty acid oxidation (FAO) pathways coupled with significant ALDH2 downregulation in DKD kidneys. Clinically, decreased ALDH2 correlated positively with tubular injury and negatively with renal function in patients. In vitro, ALDH2 knockdown markedly suppressed the activation of the PPARα signaling pathway and led to the aberrant accumulation of polyunsaturated fatty acids（PUFAs). Mechanistically, 4-HNE directly carbonylated PPARα, facilitating its ubiquitin-proteasome-dependent degradation. This post-translational modification resulted in severe FAO impairment. Conversely, pharmacological activation of ALDH2 by Alda-1 effectively cleared 4-HNE, stabilized PPARα, and significantly mitigated renal injury and tubulointerstitial fibrosis in vivo.
Conclusion
ALDH2 is a critical renal metabolic gatekeeper. Its deficiency drives DKD progression via 4-HNE-mediated PPARα carbonylation and degradation, leading to catastrophic FAO failure. Targeting the ALDH2/4-HNE/PPARα axis represents a promising precision therapeutic strategy to arrest diabetic renal fibrosis.
Acknowledgment
None
Funding
- Government Support – Non-U.S.