Abstract: FR-PO0319
HMGCS2 Drives Mitochondrial Reprogramming and Histone β-Hydroxybutyrylation in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Chen, Yuqiang, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Cao, Aili, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Fan, Ying, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Wang, Niansong, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Background
Accumulating evidence implicates mitochondrial dysfunction and epigenetic dysregulation in the progression of diabetic nephropathy (DN). 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, plays a pivotal role in mitochondrial metabolism. However, its involvement in regulating histone post-translational modifications, particularly β-hydroxybutyrylation (Kbhb), in the context of DN remains to be elucidated.
Methods
Quantitative real-time PCR and immunohistochemical analyses were performed to assess HMGCS2 expression in renal biopsy specimens from patients with established DN (n=32) and age-matched healthy controls (n=20). In vitro studies utilized human renal proximal tubular epithelial cells (HK-2) cultured under high glucose conditions (30 mM) with genetic modulation of HMGCS2 expression. Mitochondrial bioenergetics were evaluated using extracellular flux analysis, while liquid chromatography-mass spectrometry (LC-MS) was employed for metabolomic profiling. ChIP-seq and transcriptomic analysis (RNA-seq) were conducted to identify Kbhb-modified genomic loci and associated transcriptional networks. In vivo validation was performed using a streptozotocin-induced murine model of diabetes with conditional tubule-specific Hmgcs2 knockout.
Results
Renal tissues from DN patients exhibited significant upregulation of HMGCS2 expression (p<0.01), which positively correlated with histopathological indices of glomerulosclerosis and tubulointerstitial fibrosis. High glucose-stimulated HMGCS2 overexpression resulted in elevated intracellular β-hydroxybutyrate (β-OHB) concentrations, concomitant with mitochondrial fragmentation and increased reactive oxygen species production. Genome-wide mapping revealed HMGCS2-dependent enrichment of Kbhb marks at regulatory regions of pro-fibrotic genes, including TGF-β1 and COL4A1, with consequent transcriptional activation. Genetic ablation of HMGCS2 ameliorated renal Kbhb modification and attenuated DN progression, effects that were reversed by exogenous β-OHB administration.
Conclusion
This study delineates a novel pathogenic mechanism in DN wherein HMGCS2-driven mitochondrial metabolic remodeling facilitates histone β-hydroxybutyrylation, thereby exacerbating renal fibrogenesis. Therapeutic targeting of the HMGCS2/β-OHB/Kbhb axis may represent a promising strategy for DN intervention.