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PFKFB3 mediates tubular cell death in cisplatin nephrotoxicity by activating CDK4

  • Lu Wen
    Affiliations
    Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China

    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Qingqing Wei
    Affiliations
    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Man J. Livingston
    Affiliations
    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Guie Dong
    Affiliations
    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Siyao Li
    Affiliations
    Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China

    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Xiaoru Hu
    Affiliations
    Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China

    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Ying Li
    Affiliations
    Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
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  • Yuqing Huo
    Affiliations
    Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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  • Zheng Dong
    Correspondence
    Reprint requests: Zheng Dong, Tel.: +1-706-721-2825; Fax: +1-706-721-6120.
    Affiliations
    Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China

    Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

    Research Department, Charlie Norwood VA Medical Center, Augusta, Georgia, USA
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Published:October 12, 2022DOI:https://doi.org/10.1016/j.trsl.2022.10.001
      Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. However, the mechanism of cisplatin nephrotoxicity remains unclear and no effective kidney protective strategies are available. Here, we report the induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in both in vitro cell culture and in vivo mouse models of cisplatin nephrotoxicity. Notably, PFKFB3 was mainly induced in the nucleus of kidney tubular cells, suggesting a novel function other than its canonical role in glycolysis. Both pharmacological inhibition and genetic silencing of PFKFB3 led to the suppression of cisplatin-induced apoptosis in cultured renal proximal tubular cells (RPTCs). Moreover, cisplatin-induced kidney injury or nephrotoxicity was ameliorated in renal proximal tubule-specific PFKFB3 knockout mice. Mechanistically, we demonstrated the interaction of PFKFB3 with cyclin-dependent kinase 4 (CDK4) during cisplatin treatment, resulting in CDK4 activation and consequent phosphorylation and inactivation of retinoblastoma tumor suppressor (Rb). Inhibition of CDK4 reduced cisplatin-induced apoptosis in RPTCs and kidney injury in mice. Collectively, this study unveils a novel pathological role of PFKFB3 in cisplatin nephrotoxicity through the activation of the CDK4/Rb pathway, suggesting a new kidney protective strategy for cancer patients by blocking PFKFB3.

      Abbreviations:

      AKI (acute kidney injury), BUN (blood urea nitrogen), CKD (chronic kidney disease), CDKs (cyclin-dependent kinases), CDK4 (cyclin-dependent kinase 4), F2,6P2 (fructose-2,6-bisphosphate), Kim-1 (kidney injury molecule-1), OXPHOS (oxidative phosphorylation), PFK-1 (6-phosphofructo-1-kinase), PFK15 (1-(4pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), p-Rb (phosphorylated Rb), Rb (retinoblastoma tumor suppressor), RPTCs (rat renal proximal tubular cells), SCr (serum creatinine), TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)
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