Abstract: TH-PO1093
Glycolysis-Induced Advanced Glycation End Products Promote Tubular Senescence and Maladaptive Kidney Repair after Ischemic Injury
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Wei, Qingqing, Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
- Dong, Zheng, Augusta University Department of Cellular Biology and Anatomy, Augusta, Georgia, United States
Background
Maladaptive kidney repair is accompanied by the metabolic switch to glycolysis. In our study, specific knockout of renal tubule PKM2 (PKM2-KO), a key enzyme in glycolysis, ameliorated maladaptive kidney repair after ischemic injury.
Methods
In PKM2-KO mouse kidneys, we observed higher levels of GSH, likely due to the metabolic flux shift to the pentose phosphate pathway (PPP), a branched pathway producing NADPH and GSH. One consequence of this metabolic shifting could be the neutralization of methylglyoxal (MG, a major by-product of glycolysis) by PPP-derived GSH. MG is a reactive carbonyl species, which binds to various biomolecules (e.g. proteins, nucleic acids, and lipids) to form advanced glycation endproducts (AGEs), causing cellular dysfunction such as senescence in renal tubular cells.
Results
Consistently, we found that senescence was significantly induced in kidneys after 30 minutes ischemia and 2 weeks of reperfusion, showing higher SA-b-Gal staining and P16 expression (senescence markers). Meanwhile, there was dramatic AGEs induction, as demonstrated by the immunoblots and immunohistochemical staining in kidneys. PKM2-KO significantly suppressed the induction of P16 and AGEs. In cultured renal proximal tubular cells, MG induced P16 and promoted the expression of fibronectin after TGF-b1 treatment. Furthermore, AG1, an activator of the key enzyme glucose 6 phosphate dehydrogenase in PPP, enhanced wound healing in a scratch wound model of cultured renal proximal tubular cells.
Conclusion
In conclusion, these data suggest that metabolic switch to glycolysis may induce MG/AGEs in proximal tubule cells, exacerbating the senescence to promote maladaptive kidney repair.
Funding
- NIDDK Support