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Abstract: SA-PO970

Glycolysis Regulates Kidney Repair After Ischemic Injury Through the Modulation of Intracellular pH and β-Catenin Expression

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Wei, Qingqing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background

After acute injury, kidney will try to heal itself by preservation of functional renal cells and the failed renal repair may promote chronic kidney dysfunction. Meanwhile, the metabolism switch from oxidative phosphorylation to glycolysis has been noted in kidneys post-injury and experiencing chronic dysfunction. However, the role of glycolysis in kidney repair is unknown.

Methods

In this study, we tested a mouse model with inducible PKM2 (a key enzyme of glycolysis) knockout in renal tubular cells and found that these mice had similar level of renal fibrosis but better preserved renal proximal tubules and better renal function after 30 minutes of unilateral kidney ischemia and 2-week reperfusion (UI30/2wk) comparing to their wild-type litter mates, suggesting that glycolysis inhibition in renal tubules may enhance renal repair. Since glycolysis induction will lead to lactate accumulation and acidosis in kidney, we further explored whether the decreased intracellular pH can suppress wound healing and kidney repair.

Results

In vitro in cultured renal proximal tubule cells (RPTCs) with hypoxia treatment, when intracellular lactate accumulation was induced by α-Cyano-4-hydroxycinnamic acid (CyA), there was significant intracellular pH decrease, which was partially reversed by glycolysis inhibition (shikonin to inhibit PKM2) or NH4Cl to enhance intracellular pH. Concurrently, the scratched wound was healed much slower with CyA, accompanied with b-catenin increase. Either shikonin or NH4Cl improved the wound healing speed with declined b-catenin. The delayed wound healing by CyA treatment was significantly enhanced if b-catenin was knockdown. In mice, the lactate was significantly accumulated after UI30/2wk in wild type kidney, which was relieved by PKM2 knockout. The accumulation of lactate in wild type kidneys after UI30/2wk was associated with b-catenin induction but less significant in PKM2 knockout kidneys. When renal acidosis was reduced by NaHCO3 treatment at 4 days after kidney ischemia, the mice showed better renal function and significantly more intact renal proximal tubules in kidney after 2-week reperfusion.

Conclusion

Altogether, the enhanced glycolysis after acute kidney injury may intracellular pH decrease with lactate accumulation, which will further suppress renal repair, potentially through the induction of b-catenin.

Funding

  • NIDDK Support