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Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs

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Abstract

Diabetic nephropathy (DN) is the major cause of chronic kidney disease in developed countries and contributes significantly to increased morbidity and mortality among diabetic patients. Morphologically, DN is characterized by tubulo-interstitial fibrosis, thickening of the glomerular basement membrane and mesangial expansion mainly due to accumulation of extracellular matrix (ECM). ECM turnover is regulated by metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) activities. In diabetic conditions, TIMP3 expression in kidney is strongly reduced, but the causes of this reduction are still unknown. The aim of this study was to elucidate at least one of these mechanisms which relies on differential expression of TIMP3-targeting microRNAs (miRs) in a hyperglycemic environment either in vitro (MES13 cell line) or in vivo (mouse kidney and human biopsies). Among the TIMP3-targeting miRs, miR-21 and miR-221 were significantly upregulated in kidneys from diabetic mice compared to control littermates, and in a mesangial cell line grown in high glucose conditions. In human samples, only miR-21 expression was increased in kidney biopsies from diabetic patients compared to healthy controls. The expression of miR-217, which targets TIMP3 indirectly through downregulation of SirT1, was also increased in diabetic kidney and MES13 cell line. In agreement with these result, SirT1 expression was reduced in mouse and human diabetic kidneys as well as in MES13 mesangial cell line. TIMP3 deficiency has recently emerged as a hallmark of DN in mouse and human. In this study, we demonstrated that this reduction is due, at least in part, to increased expression of certain TIMP3-targeting miRs in diabetic kidneys compared to healthy controls. Unveiling the post-transcriptional mechanisms responsible for TIMP3 downregulation in hyperglycemic conditions may orient toward the use of this protein as a possible therapeutic target in DN.

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Abbreviations

TIMP:

Tissue inhibitor of metalloproteinases

DN:

Diabetic nephropathy

STZ:

Streptozotocin

miR:

MicroRNA

PCR:

Polymerase chain reaction

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Acknowledgments

This work was supported by JDRF RRG 1-2007-665 and Fondazione Roma 2008, PRIN 2009FATXW3_002 (all to M.F.) and Ministero della Salute-Ricerca Finalizzata 2008 to L.G.

Conflict of interest

The authors declare that there is no duality of interest associated with this manuscript.

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Authors and Affiliations

  1. Department of Systems Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy

    Loredana Fiorentino, Michele Cavalera, Maria Mavilio, Rossella Menghini & Massimo Federici

  2. Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy

    Francesca Conserva & Loreto Gesualdo

  3. Center for Atherosclerosis, University Hospital Tor Vergata, Rome, Italy

    Massimo Federici

Authors
  1. Loredana Fiorentino
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  2. Michele Cavalera
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  3. Maria Mavilio
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  4. Francesca Conserva
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  5. Rossella Menghini
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  6. Loreto Gesualdo
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  7. Massimo Federici
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Corresponding author

Correspondence to Massimo Federici.

Additional information

Communicated by Renato Lauro.

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Fiorentino, L., Cavalera, M., Mavilio, M. et al. Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta Diabetol 50, 965–969 (2013). https://doi.org/10.1007/s00592-013-0492-8

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  • DOI: https://doi.org/10.1007/s00592-013-0492-8

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