Abstract
Extracellular adenosine formed by 5′-ectonucleotidase (CD73) is involved in tubulo-glomerular feedback in the kidney but is also known to be an important immune modulator. Since CD73−/−mutant mice exhibit a vascular proinflammatory phenotype, we asked whether long term lack of CD73 causes inflammation related kidney pathologies. CD73−/−mice (13 weeks old) showed significantly increased low molecule proteinuria compared to C57BL6 wild type controls (4.8≥0.52 vs. 2.9±0.54 mg/24 h, p<0.03). Total proteinuria increased to 5.97±0.78 vs. 2.55±0.35 mg/24 h at 30 weeks (p<0.01) whereas creatinine clearance decreased (0.161±0.02 vs. 0.224±0.02 ml/min). We observed autoimmune inflammation in CD73−/−mice with glomerulitis and peritubular capillaritis, showing glomerular deposition of IgG and C3 and enhanced presence of CD11b, CD8, CD25 as well as GR-1-positive cells in the interstitium. Vascular inflammation was associated with enhanced serum levels of the cytokines IL-18 and TNF-α as well as VEGF and the chemokine MIP-2 (CXCL-2) in CD73−/−mice, whereas chemokines and cytokines in the kidney tissue were unaltered or reduced. In CD73−/−mice glomeruli, we found a reduced number of podocytes and endothelial fenestrations, increased capillaries per glomeruli, endotheliosis and enhanced tubular fibrosis. Our results show that adult CD73−/−mice exhibit spontaneous proteinuria and renal functional deterioration even without exogenous stress factors. We have identified an autoimmune inflammatory phenotype comprising the glomerular endothelium, leading to glomeruli inflammation and injury and to a cellular infiltrate of the renal interstitium. Thus, long term lack of CD73 reduced renal function and is associated with autoimmune inflammation.
Highlights
While the intracellular formation of adenosine predominates under hypoxic conditions, its extracellular formation results from the degradation of extracellular adenine nucleotides by action of CD39/ecto-apyrase and CD73/ecto-59-nucleotidase [1,2]
The proteinuria/creatininuria ratio was significantly increased in 9 weeks old male CD732/2mice (p,0.03) and remained increased up to 30 weeks (Figure 1C, left panel)
Compared to WT controls, male CD732/2mice exhibited increased level of total protein in urine already at 9 weeks of age, and a significant increase in total proteinuria was observed at the age of 13 weeks (4.8060.52 mg/24 h vs. 2.9760.54 mg/24 h; p,0.03), 22 weeks (5.9760.78 vs. 2.5560.35 mg/24 h in WT controls; p,0.01) and 30 weeks (5.8360.651 vs. 1.8360.651 mg/ 24 h in WT controls; p,0.0002; Figure 1C, right panel)
Summary
While the intracellular formation of adenosine predominates under hypoxic conditions, its extracellular formation results from the degradation of extracellular adenine nucleotides by action of CD39/ecto-apyrase and CD73/ecto-59-nucleotidase [1,2]. CD73-deficient (CD732/2) mice were independently generated in the last few years by three laboratories and have provided growing evidence that CD73-derived adenosine participates in numerous important biological functions, such as playing a crucial role in hypoxia-induced vascular leakage [5] and tissue protection as shown in a model of bleomycin-induced lung injury [6]. The distribution of adenosine receptors in the kidney is only incompletely defined due to the cellular complexity of the kidney and the low expression levels [9]. CD73-derived adenosine has been shown to be renoprotective in a model of diabetic glomerulopathy, where stimulation of the A2A receptor resulted in structural improvement [19], possibly by stabilization of podocytes, blocking podocyte permeability and actin disruption [20]. A2A receptor activation was found to be protective against renal injury in a mouse model of lupus nephritis (MRL/lpr mice) [21]
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