The TGF-β profibrotic cascade targets ecto-5'-nucleotidase gene in proximal tubule epithelial cells and is a traceable marker of progressive diabetic kidney disease.

Abstract

Progressive diabetic nephropathy (DN) and loss of renal function correlate with kidney fibrosis. Crosstalk between TGF-β and adenosinergic signaling contributes to the phenotypic transition of cells and to renal fibrosis in DN models. We evaluated the role of TGF-β on NT5E gene expression coding for the ecto-5`-nucleotidase CD73, the limiting enzyme in extracellular adenosine production. We showed that high d-glucose may predispose HK-2 cells towards active transcription of the proximal promoter region of the NT5E gene while additional TGF-β results in full activation. The epigenetic landscape of the NT5E gene promoter was modified by concurrent TGF-β with occupancy by the p300 co-activator and the phosphorylated forms of the Smad2/3 complex and RNA Pol II. Transcriptional induction at NT5E in response to TGF-β was earlier compared to the classic responsiveness genes PAI-1 and Fn1. CD73 levels and AMPase activity were concomitantly increased by TGF-β in HK-2 cells. Interestingly, we found increased CD73 content in urinary extracellular vesicles only in diabetic patients with renal repercussions. Further, CD73-mediated AMPase activity was increased in the urinary sediment of DN patients. We conclude that the NT5E gene is a target of the profibrotic TGF-β cascade and is a traceable marker of progressive DN.

• Authors: Claudio Cappelli, Analia Tellez, Claudia Jara, Sebastián Alarcón, Angelo Torres, Pablo Mendoza, Loreto Podestá, Claudio Flores, Claudia Quezada, Carlos Oyarzún, Rody San Martín
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1866 Issue 7 Pg. 165796 (07 01 2020) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 32289379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• GPI-Linked Proteins
• Transforming Growth Factor beta
• E1A-Associated p300 Protein
• EP300 protein, human
• RNA Polymerase II
• Nucleotidases
• adenosine monophosphatase
• 5'-Nucleotidase
• NT5E protein, human
• Adenosine

Topics

• 5'-Nucleotidase (genetics)
• Adenosine (biosynthesis)
• Biomarkers (metabolism)
• Cell Line
• Diabetic Nephropathies (genetics, pathology)
• E1A-Associated p300 Protein (genetics)
• Epigenesis, Genetic (genetics)
• Epithelial Cells (metabolism, pathology)
• Fibrosis (genetics, pathology)
• GPI-Linked Proteins (genetics)
• Gene Expression Regulation
• Humans
• Kidney (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism, pathology)
• Nucleotidases (genetics)
• Promoter Regions, Genetic (genetics)
• RNA Polymerase II (genetics)
• Transforming Growth Factor beta (genetics)