Autoimmunity in CD73/Ecto-5'-nucleotidase deficient mice induces renal injury.
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.
Division of Nephrology, Department of Medicine, Hannover Medical School, Hannover, Germany. Blume.cornelia@mh-hannover.de
Cornelia
C
Blume
Agnieszka
A
Felix
Nelli
N
Shushakova
Faikah
F
Gueler
Christine Susanne
CS
Falk
Hermann
H
Haller
Juergen
J
Schrader
D015720:5'-Nucleotidase / Q000172:deficiency* / Q000378:metabolism; D058186:Acute Kidney Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D002196:Capillaries / Q000378:metabolism; D002452:Cell Count; D054426:Chemokine CXCL2 / Q000097:blood; D003176:Complement C3 / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D050527:Mesangial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010641:Phenotype; D050199:Podocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D054426:Chemokine CXCL2; D003176:Complement C3; D007074:Immunoglobulin G; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D015720:5'-Nucleotidase; D000241:Adenosine