Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-β activity and TGF-β1 expression

F. Oriente, S. Iovino, A. Cassese, C. Romano, C. Miele, G. Troncone, M. Balletta, A. Perfetti, G. Santulli, G. Iaccarino, R. Valentino, F. Beguinot, P. Formisano

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Aims/hypothesis: Overproduction of phosphoprotein enriched in diabetes (PED, also known as phosphoprotein enriched in astrocytes-15 [PEA-15]) is a common feature of type 2 diabetes and impairs insulin action in cultured cells and in mice. Nevertheless, the potential role of PED in diabetic complications is still unknown. Methods: We studied the effect of PED overproduction and depletion on kidney function in animal and cellular models. Results: Transgenic mice overexpressing PED (PEDTg) featured age-dependent increases of plasma creatinine levels and urinary volume, accompanied by expansion of the mesangial area, compared with wild-type littermates. Serum and kidney levels of TGF-β1 were also higher in 6- and 9-month-old PEDTg. Overexpression of PED in human kidney 2 cells significantly increased TGF-β1 levels, SMAD family members (SMAD)2/3 phosphorylation and fibronectin production. Opposite results were obtained following genetic silencing of PED in human kidney 2 cells by antisense oligonucleotides. Inhibition of phospholipase D and protein kinase C-β by 2-butanol and LY373196 respectively reduced TGF-β1, SMAD2/3 phosphorylation and fibronectin production. Moreover, inhibition of TGF-β1 receptor activity and SMAD2/3 production by SB431542 and antisense oligonucleotides respectively reduced fibronectin secretion by about 50%. TGF-β1 circulating levels were significantly reduced in Ped knockout mice and positively correlated with PED content in peripheral blood leucocytes of type 2 diabetic patients. Conclusions/interpretation: These data indicate that PED regulates fibronectin production via phospholipase D/protein kinase C-β and TGF-β1/SMAD pathways in kidney cells. Raised PED levels may therefore contribute to the abnormal accumulation of extracellular matrix and renal dysfunction in diabetes.

Original languageEnglish (US)
Pages (from-to)2642-2652
Number of pages11
Issue number12
StatePublished - Dec 2009
Externally publishedYes


  • Diabetic nephropathy
  • PEA-15
  • PED
  • PKC
  • TGF-β1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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