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ENTPD1, a Protective Vascular Ecto-Enzyme, Prevents Diabetic Nephropathy

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ENTPD1, a Protective Vascular Ecto-Enzyme, Prevents Diabetic Nephropathy Diabetes In Press, published online May 1, 2007 The Vascular Ectonucleotidase ENTPD1 is a Novel Renoprotective Factor in Diabetic Nephropathy Received for publication 14 November 2006 and accepted in revised form 25 April 2007. Short running Title: ENTPD1 Protects Against Diabetic Nephropathy David J. Friedman,1 Helmut G. Rennke,4 Eva Csizmadia,3 Keiichi Enjyoji,2 and Simon C. Robson.2,3 Renal,1 Gasteroenterology,2 and Transplantation Divisions,3 Department of Medicine, Beth Israel Deaconess Medical Center. Department of Pathology, Brigham and Women's Hospital.4 Harvard Medical School, Boston, Massachusetts. Address Correspondence to: David J. Friedman Department of Medicine Beth Israel Deaconess Medical Center Harvard University Research North 359 99 Brookline Avenue Boston, MA. 02215 [email protected] OR: Simon C. Robson Department of Medicine Beth Israel Deaconess Medical Center Harvard University Research North 301 99 Brookline Avenue Boston, MA. 02215 [email protected] 1 Copyright American Diabetes Association, Inc., 2007 ABSTRACT 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 sub-acute 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 as compared to 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 ATPγS stimulated sustained expression of PAI-1 and MCP-1 in vitro, while the stable adenosine analog NECA 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. 2 Diabetic Nephropathy is the leading such as renal ischemia- cause of renal failure in the United reperfusion(14; 15) and transplant States.(1) Currently, over 160,000 rejection.(16; 17) Americans suffer from End-Stage Renal Disease (ESRD) due to In this study, we hypothesized that diabetes with the five-year mortality in aberrant nucleotide signaling in the these patients approaching 70%.(1; 2) absence of ENTPD1 might promote It is unknown why only 1 in 3 patients chronic microvascular injury in with diabetes develop nephropathy. diabetic nephropathy. Our hypothesis Hypertension and glycemic control are was bolstered by the previous finding important risk factors, but genetic pre- that PC-1, another ectonucleotidase disposition may be the most powerful expressed in the kidney that predictor of ESRD from diabetes.(3-5) metabolizes ATP to AMP + Mouse models allow candidate pyrophosphate, has been associated susceptibility genes to be with diabetic nephropathy in human independently evaluated while genetic association studies.(18; 19) preserving the complex architecture of ENTPD1 similarly hydrolyzes the pro- the mammalian glomerulus. inflammatory molecule ATP and initiates an ecto-enzymatic cascade ENTPD1 (Ecto-nucleoside that leads to generation of adenosine, Triphosphate Diphosphohydrolase-1, which has predominantly anti- also known as CD39) is a vascular inflammatory properties. Interestingly, ectoenzyme expressed by endothelial adenosine A2a agonists such as ATL cells and smooth muscle.(6; 7) This 146e appear protective in diabetic nucleotidase metabolizes extracellular nephropathy models in mice.(20) ATP and ADP to AMP (as well as UTP and UDP to UMP), which is Numerous pathways have been subsequently converted to adenosine associated with development of by the ecto-enzyme CD73. (8) By diabetic nephropathy in rodents and controlling extracellular nucleotide humans. Among the most intriguing levels, ENTPD1 regulates the are the interrelated pathways of activation of type-2 purinergic inflammation and thromboregulation. receptors (P2X and P2Y— ligand- Absence of ENTPD1 in null mice gated and G-protein coupled results in increased tissue factor receptors respectively) involved in expression in the vasculature and many cellular processes including increased fibrin deposition in multiple thrombosis, inflammation, organs including the kidney.(21) angiogenesis, cellular proliferation, ENTPD1-null mice are also more and apoptosis.(9-12) ENTPD1 is prone to inflammation both in the highly expressed in the kidney, basal state and in injury models.(22) including the larger vessels, afferent We suspected that any tipping of the arterioles, and glomeruli.(13) We purinergic balance toward have previously shown that ENTPD1 inflammation and fibrin deposition is a protective factor in several acute would result in heightened sensitivity and sub-acute vascular injury models to renal injury in the context of 3 hyperglycemia from superimposed were approved by the Institutional diabetes. We tested this hypothesis Animal Care and Use Committee at using the streptozocin (STZ)-induced Beth Israel Deaconess Medical model of type 1 diabetes on wild-type Center. mice and mice null for ENTPD1. Measurement of albumin and creatinine. Serum creatinine was RESEARCH DESIGN AND measured by High Performance Liquid METHODS Chromotography (HPLC) at the Mouse Metabolic Phenotyping Center STZ-induced diabetes. ENTPD1-null at Vanderbilt University. Urinary mice were originally generated on a albumin was measured by mouse- mixed C57BL6/129S background(21) specific ELISA (Albuwell M, Exocell). and subsequently backcrossed >6 Urinary creatinine was measured by times onto a C57BL6 background. 8 colorimetic reaction (Creatinine week old ENTPD1-null male mice Companion, Exocell). and age, sex, and weight-matched wild-type mice on the C57/BL6 Histology. Mouse kidneys were fixed background were used in these in 10% buffered formalin followed by experiments. Mice were given two embedding in paraffin. Three consecutive daily intraperitoneal micrometer sections were stained with injections of 75 mg/kg of periodic acid-Schiff (PAS). Sections Streptozotocin (STZ) in 50 mM citrate were read in a blinded manner by a buffer or citrate buffer alone (control nephrologist and renal pathologist. 6- groups) after a 3 hour fast. Glucose 11 mice were scored per group. Fifty was checked 3 weeks after STZ glomeruli were scored per mouse and injection and mice with glucose levels averaged. A sclerosis index (0-4) to between 300-550 mg/dL were assess diabetic glomerular injury was selected for the experiment. Glucose developed as follows: 0=normal measurements were made with glomeruli, 1=mild mesangial Gluco-elite. Urine was collected at 12 expansion/injury (<20% PAS positive), and 24 weeks post STZ. Blood 2=moderate injury (20-40% PAS pressure was measured by tail cuff positive), 3=severe injury (40-60% manometry (BP-2000 Blood Pressure PAS positive), 4=global sclerosis Analysis System, Visitech Systems) (>60% PAS positive). for seven consecutive days; >10 measurements over a 20 minute Immunohistochemistry. Tissue was period were averaged per day. The harvested and frozen in liquid first five days constituted the training nitrogen/isopentane (for ENTPD1, period and the reported blood fibrin, CD31) or fixed for 36 hours in a pressure is the average of the final zinc-based fixative(23) (for PAI-1). two sessions (days 6 and 7). Animals For frozen tissue, 5 micron sections were sacrificed at 24 weeks with blood were fixed in 4°C acetone for 10 and kidney tissue harvested at that minutes for light microscopy or fixed in time. Animal studies were conducted 2% paraformaldehyde for 15 minutes in accordance with NIH guidelines and for immunofluorescence; Zinc-fixed 2 tissue for light microscopy was post- glomerulus and 4=global, heavy PAI-1 fixed in 2% paraformaldehyde for 15 staining in glomerulus. 4 mice were minutes. PAI-1 antibody (sheep anti- examined (reader blinded to grouping) mouse, 1:750) was purchased from per group. American Diagnostica. Fibrin antibody (rabbit anti-mouse, 1:15,000) Real-Time PCR. RNA was isolated was purchased from Dako and from renal cortex or cultured required citrate buffer or Triton pre- mesangial cells using the RNeasy kit treatment. ENTPD1 antibody (C9F, from Invitrogen. 0.5 to1 ug of RNA 1:1,000) is a rabbit anti-mouse was reverse transcribed to cDNA polyclonal antibody generated by using the Taqman Reverse cDNA immunization in our laboratory. Transcription Kit from Applied CD31 antibody (rat anti-mouse, Biosystems. PAI-1 1mg/ml) was purchased from BD (Mm00435860_m1) and MCP-1 Pharmigen. Biotinylated secondary (Mm00441242_m1) Primer-probe sets antibodies for light microscopy (goat and Taqman Universal PCR anti-rabbit, 2mg/ml; rabbit anti-sheep, Mastermix were purchased from 2mg/ml) were purchased from Vector. Applied Biosystems. cDNA was For light microscopy, after initial amplified using an ABI PRISM
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