Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

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.

Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

“…CD73-null mice spontaneously develop autoimmune diseases such as glomerulitis and peritubular capillaritis, accompanied by enhanced inflammation (Blume et al, 2012). They are also susceptible to polymicrobial sepsis induced by cecal ligation and puncture, and exhibit increased mortality and systemic inflammation (Hasko et al, 2011).…”

Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect

“…Podocytes and mesangial cells are two of the major cell lineages in the renal glomerulus (27). To delineate which glomerular cell lineage expressed GATA3, we costained kidneys recovered from Gata3 g/ϩ mice with antibodies recognizing CD73 (a mesangial cell marker [28]), synaptopodin (a podocyte marker [29]), or GATA3-GFP expressed from the Gata3 g targeted allele. These colocalization studies demonstrated that a large proportion of GATA3-GFP-positive cells coexpressed CD73 (Fig.…”

Danger Signals From ATP and Adenosine in Pregnancy and Preeclampsia

“…86 Recent unpublished pilot studies in our laboratory showed that infusion of ATP (for 1 hour on day 14 of pregnancy) in pregnant rats induced a slight but significant increase in blood pressure until 48 hours after infusion. In addition, CD73 knockout mice, which are likely to have elevated ATP levels, display preeclampsia-like symptoms, such as proteinuria, inflammation, endothelial dysfunction, and glomerular endotheliosis, [87][88][89] whereas CD39 overexpression inhibited the induction of preeclampsia in mice. 90 …”