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Emerging role of tumor suppressor p53 in acute and chronic kidney diseases

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Abstract

p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in the initiation and progression of several renal diseases, which is the focus of this review. Ischemic-, aristolochic acid (AA) -, diabetic-, HIV-associated-, obstructive- and podocyte-induced nephropathies are accompanied by activation and/or elevated expression of p53. Studies utilizing chemical or renal-specific inhibition of p53 in mice confirm the pathogenic role of this transcription factor in acute kidney injury and chronic kidney disease. TGF-β1, NOX, ATM/ATR kinases, Cyclin G, HIPK, MDM2 and certain micro-RNAs are important determinants of renal p53 function in response to trauma. AA, cisplatin or TGF-β1–mediated ROS generation via NOXs promotes p53 phosphorylation and subsequent tubular dysfunction. p53-SMAD3 transcriptional cooperation downstream of TGF-β1 orchestrates induction of fibrotic factors, extracellular matrix accumulation and pathogenic renal cell communication. TGF-β1-induced micro-RNAs (such as mir-192) could facilitate p53 activation, leading to renal hypertrophy and matrix expansion in response to diabetic insults while AA-mediated mir-192 induction regulates p53 dependent epithelial G2/M arrest. The widespread involvement of p53 in tubular maladaptive repair, interstitial fibrosis, and podocyte injury indicate that p53 clinical targeting may hold promise as a novel therapeutic strategy for halting progression of certain acute and chronic renal diseases, which affect hundreds of million people worldwide.

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Funding

Supported by NIH Grant GM057242 to PJH and a Capital District Medical Research Institute Grant to RS.

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Authors and Affiliations

  1. Eli Lilly and Company, Indianapolis, IN, USA

    Jessica M. Overstreet

  2. Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA

    Cody C. Gifford, Paul J. Higgins & Rohan Samarakoon

  3. Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA

    Jiaqi Tang

  4. Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA

    Paul J. Higgins & Rohan Samarakoon

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  1. Jessica M. Overstreet
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  2. Cody C. Gifford
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  4. Paul J. Higgins
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Correspondence to Paul J. Higgins or Rohan Samarakoon.

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Overstreet, J.M., Gifford, C.C., Tang, J. et al. Emerging role of tumor suppressor p53 in acute and chronic kidney diseases. Cell. Mol. Life Sci. 79, 474 (2022). https://doi.org/10.1007/s00018-022-04505-w

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