Acta Diabetologica

, Volume 50, Issue 6, pp 965–969 | Cite as

Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs

  • Loredana Fiorentino
  • Michele Cavalera
  • Maria Mavilio
  • Francesca Conserva
  • Rossella Menghini
  • Loreto Gesualdo
  • Massimo Federici
Original Article

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.

Keywords

Diabetic Nephropathy MicroRNA TIMP3 SirT1 

Abbreviations

TIMP

Tissue inhibitor of metalloproteinases

DN

Diabetic nephropathy

STZ

Streptozotocin

miR

MicroRNA

PCR

Polymerase chain reaction

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Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  • Loredana Fiorentino
    • 1
  • Michele Cavalera
    • 1
  • Maria Mavilio
    • 1
  • Francesca Conserva
    • 2
  • Rossella Menghini
    • 1
  • Loreto Gesualdo
    • 2
  • Massimo Federici
    • 1
    • 3
  1. 1.Department of Systems MedicineUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Department of Emergency and Organ TransplantationUniversity of BariBariItaly
  3. 3.Center for AtherosclerosisUniversity Hospital Tor VergataRomeItaly

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