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The Vascular Ectonucleotidase ENTPD1 Is a Novel Renoprotective Factor in Diabetic Nephropathy

¹ Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
³ Transplantation Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
⁴ Gastroenterology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to David J. Friedman, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Research North 359, 99 Brookline Ave., Boston, MA 02215. E-mail: dfriedma{at}caregroup.harvard.edu. Or to Simon C. Robson, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Research North 301, 99 Brookline Ave., Boston, MA 02215. E-mail: srobson{at}bidmc.caregroup.edu

Abbreviations: BIM, bisindolylmaleimide I; ENPP1/PC-1, ectonucleotide pyrophosphatase/ phosphodiesterase-1; ENTPD1, ectonucleoside triphosphate diphosphohydrolase 1; HPLC, high-performance liquid chromotography; MCP-1, monocyte chemoattractant protein-1; NECA, 5'-(N-ethylcarboxamido)adenosine; PAI-1, plasminogen activator inhibitor-1; PAS, periodic acid Schiff; STZ, streptozotocin

Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute models of vascular injury. We hypothesized that aberrant nucleotide signaling would promote chronic glomerular injury in diabetic nephropathy. Inducing diabetes in ENTPD1-null mice with streptozotocin resulted in increased proteinuria and more severe glomerular sclerosis compared with matched diabetic wild-type mice. Diabetic ENTPD1-null mice also had more glomerular fibrin deposition and glomerular plasminogen activator inhibitor-1 (PAI-1) staining than wild-type controls. In addition, ENTPD1-null mice showed increased glomerular inflammation, in association with higher levels of monocyte chemoattractant protein-1 (MCP-1) expression. Mesangial cell PAI-1 and MCP-1 mRNA expression were upregulated by ATP and UTP but not ADP or adenosine in vitro. The stable nucleotide analog ATPS stimulated sustained expression of PAI-1 and MCP-1 in vitro, whereas the stable adenosine analog NECA [5'-(N-ethylcarboxamido)adenosine] downregulated expression of both genes. Extracellular nucleotide-stimulated upregulation of MCP-1 is, at least in part, protein kinase C dependent. We conclude that ENTPD1 is a vascular protective factor in diabetic nephropathy that modulates glomerular inflammation and thromboregulation.

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				K. Enjyoji, K. Kotani, C. Thukral, B. Blumel, X. Sun, Y. Wu, M. Imai, D. Friedman, E. Csizmadia, W. Bleibel, et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance Diabetes, September 1, 2008; 57(9): 2311 - 2320. [Abstract] [Full Text] [PDF]