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Original article
Vascular expression of annexin A2 in lupus nephritis
  1. V Salle1,
  2. C Cordonnier2,
  3. J Schmidt1,
  4. C Mazière3,
  5. A Smail1,
  6. C Attencourt2,
  7. M P Mabille2,
  8. J C Mazière3,
  9. R Makdassi4,
  10. G Choukroun4,
  11. M Diouf5,
  12. P Duhaut1,
  13. J P Ducroix1
  1. 1Department of Internal Medicine, Amiens University Hospital, Amiens, France
  2. 2Department of Pathology, Amiens University Hospital, Amiens, France
  3. 3INSERM U1088 Biochemistry Laboratory, Amiens University Hospital, Amiens, France
  4. 4Department of Nephrology, Amiens University Hospital, Amiens, France
  5. 5Division of Clinical Research and Innovation, Amiens University Hospital, Amiens, France
  1. Correspondence to Dr V Salle, Department of Internal Medicine, Amiens University Hospital, F-80054 Amiens cedex 1, France; salle.valery{at}chu-amiens.fr

Abstract

Aims To evaluate vascular expression of annexin A2 (ANXA2) and its subunit S100A10 in lupus nephritis (LN).

Methods The present histological study included 14 patients with LN and 11 controls (patients with non-lupus kidney diseases). Kidney biopsies from patients with lupus were scored for lupus glomerulonephritis (according to the International Society of Nephrology/Renal Pathology Society 2003 classification) and vascular lesions (such as microthrombi and antiphospholipid syndrome nephropathy (APSN)). ANXA2 and S100A10 expression in glomerular and peritubular capillaries was evaluated by immunohistochemistry on tissue sections. The staining intensity score ranged from 0 (no expression) to 4 (intense expression).

Results In patients with LN, the median age (range) at first kidney biopsy was 36 (18–49). Vascular lesions were observed in six patients (including two with APSN). We observed intense expression of ANXA2 in glomerular and peritubular capillaries while expression of S100A10 was weaker. However, one of the patients with APSN showed strong S100A10 expression. Patients with LN and controls differed significantly in terms of S100A10 expression in peritubular capillaries. We also observed a statistical difference between patients who had LN with renal vascular lesions and those without renal vascular lesions in terms of ANXA2 expression in peritubular capillaries.

Conclusions The presence of vascular lesions in LN appears to be associated with significant differences in the vascular expression of ANXA2. Vascular expression of ANXA2 was somewhat higher in LN. Vascular expression of S100A10 was somewhat lower in LN (except one of the two patients with APSN). Further studies of ANXA2's putative value as a biomarker of active LN or of vascular lesions in LN are required.

  • LUPUS
  • ANTIPHOSPHOLIPID
  • IMMUNOHISTOCHEMISTRY

https://doi.org/10.1136/jclinpath-2015-203139

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    Introduction

    Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease characterised by a broad spectrum of clinical features and the production of autoantibodies against nuclear, cytoplasmic and cell membrane target antigens.1 Lupus nephritis (LN) is one of the most serious manifestations of SLE and has a marked impact on mortality and morbidity. Active nephropathy was diagnosed in 28% of the patients in the prospective Euro-Lupus cohort, and the prevalence reported in American and Asian series are higher still.2 Anti-DNA antibodies have a harmful role in LN, with the formation of glomerular immune complexes that activate complement and lead to inflammation.3 Although kidney disease is most frequently characterised by the presence of glomerulonephritis, tubulointerstitial and vascular lesions (such as microthrombosis) may also be present. Glomerular thrombosis is associated with more active, more severe lesions and represents a prognostic factor for the development of sclerosis.4 ,5 The pathogenesis of glomerular microthrombosis in patients with LN has not been characterised. The association between glomerular microthrombosis and antiphospholipid syndrome (APS) is controversial. Various intrarenal vascular lesions have been linked to primary APS, and antiphospholipid syndrome nephropathy (APSN) is histologically characterised by acute lesions (such as thrombotic microangiopathy) and chronic lesions.6 Elevated expression of type 1 plasminogen activator inhibitor (PAI-1) was observed in the kidney of female MRL/lpr mice with LN.7 An epistatic interaction between PAI-1 and β-fibrinogen modifies the risk of glomerular thrombosis.8 Several studies have reported that impaired fibrinolysis may be associated with an elevated risk of thrombosis in patients with SLE.9

    Annexin A2 (ANXA2, 36 kD) belongs to the annexin superfamily of Ca2+-regulated phospholipid-binding proteins.10 It exists as a monomer or a heterotetrameric complex with S100A10 protein (a member of the S100 family, sometimes referred to as p11).11 High ANXA2 expression has been reported in intestine, lung, vascular tissue and placenta.12 ANXA2 is involved in several biological processes, including exocytosis, endocytosis, cell migration, lipid raft organisation and ion channel regulation.13 ,14 It has also been identified as a coreceptor for tissue plasminogen activator and plasminogen on the endothelial cell surface.15 The S100A10 subunit also has a key role in plasminogen binding and cell surface plasmin generation.16 ANXA2 has a pivotal role in the pathogenesis of APS. Endothelial cell activation by anti-β2 glycoprotein I antibodies is mediated by a multiprotein signalling complex that includes ANXA2.17 Last, ANXA2 has also been identified as a new autoantigen in APS, although the nature of its immunodominant epitopes has yet to be defined.18–20 These findings prompted us to evaluate the vascular expression of ANXA2 and the S100A10 subunit in LN.

    Patients and methods

    Patients

    A total of 14 patients with LN were included retrospectively. The patients were monitored at the Department of Internal Medicine and Nephrology at Amiens University Hospital (Amiens, France). All patients underwent kidney biopsy and fulfilled the American College of Rheumatology's revised criteria for SLE.21 Patients with lupus with APS satisfied the revised classification criteria for this syndrome.22 Eleven patients with non-lupus kidney diseases were recruited as controls by the above-mentioned nephrology department; their kidney biopsies variously revealed focal and segmental hyalinosis, IgA nephropathy, tubulointerstitial nephritis, membranous glomerulonephritis, minimal change disease, cortical atrophy and glomerulosclerosis. Demographic data were collected for all patients.

    The following histological data were recorded for each kidney biopsy of patients with LN: subtypes of glomerular involvement in SLE (according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification23) and vascular lesions (such as glomerular microthrombosis and APSN).

    Vascular expression of ANXA2 and its light chain S100A10 in kidney biopsy tissue

    To evaluate the expression of ANXA2 and S100A10 in glomerular and peritubular capillaries, we performed an immunohistochemical assessment of tissue sections fixed in Duboscq-Brasil fluid and embedded in paraffin. Cryosections (2–3 μm thick) were then incubated with monoclonal mouse anti-annexin II antibody (Invitrogen, Camarillo, California, USA; clone ZO14) and purified mouse anti-annexin II light chain antibody (BD Biosciences, San Jose, California, USA; clone 148) diluted at 1:1500 for 32 min. The slides were then incubated with biotinylated secondary antibody for 8 min and then with streptavidin horseradish peroxidase for 8 min. Lastly, slides were counterstained with haematoxylin. Immunohistochemical staining was evaluated using a score of 0–4 as negative (0), weak (1), moderate (2), strong (3) and intense (4).

    Statistical analysis

    Quantitative variables were expressed as median values (range) and qualitative variables as percentage. Wilcoxon rank sum test was used to compare the group of control subjects and the group of patients with LN in terms of the ANXA2 and S100A10 vascular expression score. Wilcoxon rank sum test was also used to compare the group of patients with LN with renal vascular lesions and the group of patients with LN without renal vascular lesions in terms of the ANXA2 and S100A10 vascular expression score.

    p Values were two sided, and the statistical threshold for significance was set to 0.05.

    All statistical analyses were performed with R.3.1.0.

    Results

    Characteristics of the study population

    All of the 14 patients with LN were female. Secondary APS was present in four patients. The median age (range) at the time of first biopsy was 36 (18–49). Five patients had at least 2 kidney biopsies, and we studied a total of 20 kidney biopsies. All control patients (six women and five men) had one kidney biopsy, and their median age (range) at the time of biopsy was 55 (30–79). Class III or IV LN was most frequent (table 1).

    View this table:
    Table 1

    Histological findings in renal biopsies

    Of the patients with LN, one was class (II+V), one was class (IV+V) and none was class I or class VI. Glomerular microthrombosis was observed in four patients and APSN was detected in two patients.

    Vascular expression of ANXA2 and S100A10 in renal tissues

    Most of the kidney biopsies displayed intense staining (ie, a score of 4) for ANXA2 in sections from glomerular and peritubular capillaries (figures 1 and 2). The staining intensity for S100A10 was weaker (a score of 1) in peritubular capillaries (table 2).

    View this table:
    Table 2

    Vascular expression of ANXA2 and S100A10 in kidney biopsies from patients with LN and controls

    Figure 1
    Figure 1

    Intense ANXA2 expression in a kidney biopsy from a patient with antiphospholipid syndrome nephropathy and class III/C lupus nephritis, showing granular staining of ANXA2 in peritubular capillaries. Magnification: ×200.

    Figure 2
    Figure 2

    ANXA2 expression in a kidney biopsy from a patient with class V lupus nephritis, showing intense staining in glomerular and peritubular capillaries. Magnification: ×200.

    There was no detectable S100A10 expression in glomerular capillaries in 61% of the kidney biopsies (table 2). Moderate S100A10 expression in glomerular and peritubular capillaries (figure 3) was only seen in 16% and 15% of the kidney biopsies, respectively (table 2). Strong staining for S100A10 in peritubular capillaries was only observed for one patient—one of the individuals with APSN (figure 4). There was no significant difference between patients with LN and control subjects in terms of the vascular expression of ANXA2. However, we observed low or null vascular expression of S100A10 in renal tissues from control subjects (table 2). When comparing patients with LN and controls, there was statistically significant difference in the expression of S100A10 in peritubular capillaries (p=0.0322). There was also statistical difference between patients with LN with renal vascular lesions and those without renal vascular lesions in terms of ANXA2 expression in peritubular capillaries (p=0.008).

    Figure 3
    Figure 3

    Moderate S100A10 expression in a kidney biopsy from a patient with class IV-S (A/C), showing S100A10 staining in podocytes in active lesions and slight staining in peritubular capillaries. Magnification: ×200.

    Figure 4
    Figure 4

    Strong and moderate reactivity for S100A10 (in peritubular and glomerular capillaries, respectively) for the kidney biopsy shown in figure 1. Magnification: ×200.

    Discussion

    A number of intrarenal and extrarenal disease mechanisms are involved in the pathogenesis of LN.3 The intrarenal aetiology of LN is multifaceted and involves immune complex deposits in the glomerulus, complement activation, the production of pro-inflammatory cytokines, the infiltration of leucocytes (such as macrophages and lymphocytes) that lead to kidney damage. ANXA2 is expressed in many different tissues. Like annexins A1, A4, A5 and A13b, ANXA2 is present in the kidney.24 It has been recently identified as a glomerular target for anti-DNA antibodies.25 ANXA2 mediates the binding of anti-double-stranded DNA antibodies to mesangial cells, which in turn induces IL-6 secretion and further ANXA2 synthesis.25 Furthermore, ANXA2 is present on the endothelial cell surface, where it forms (in the presence of S100A10) a heterotetrameric complex and thus promotes vascular fibrinolysis.

    Here, we found that glomerular and peritubular vascular expression of ANXA2 was markedly upregulated in LN—even in the presence of vascular lesions, such as glomerular thrombosis and APSN. Increased vascular expression of ANXA2 was also observed in renal biopsies from controls. We did not observe any difference between LN and non-lupus kidney diseases in terms of ANXA2 vascular expression. Contrary to what we observed, Yung et al25 showed that ANXA2 was upregulated in LN but not in other renal diseases. However, all patients had diffuse proliferative LN in their study. Here, only a third of patients with LN were class IV. Furthermore, our cohort of ‘controls’ was heterogeneous with regard to the aetiology of kidney disease. Yung et al25 observed the constitutive expression of ANXA2 in the glomerulus of normal kidney. ANXA2 is also strongly expressed in vascular tissue.12 Human anti-DNA antibodies can bind to endothelial cells.26 Moreover, anti-DNA antibodies activate endothelial and mesangial cells.3 ,27 One can legitimately hypothesise that the binding of anti-DNA antibodies to endothelial cells induces ANXA2 vascular expression (as observed for mesangial cells). Elevated vascular endothelial growth factor (VEGF) plasma levels have been found in patients with LN.28 One can also hypothesise that upregulation of ANXA2 expression in endothelial cells is induced by VEGF, as has been observed in a mouse model of ischaemic retinopathy.29 Most kidney biopsies were performed during lupus flare and upregulation of renal ANXA2 expression could be associated with disease progression, as has been showed by Yung et al25 in NZBWF1/J mice.

    In contrast, the vascular expression of S100A10 in patients with LN was less intense than that observed for ANXA2. The ANXA2 heterotetramer is the predominant form on the cell surface and the S100A10 subunits are located in the centre of this complex (ie, in contact with the membrane surface).16 Our results show that expression of S100A10 in peritubular capillaries was significantly greater in LN than in non-lupus kidney diseases. The highest levels of vascular S100A10 expression were observed in a patient with APSN. Thrombin induces endothelial cell surface exposure of S100A10.30 A recent study shows that interferon (INF)-γ stimulation induces surface expression of S100A10 on lung epithelial cells.31 One can hypothesise that expression of S100A10 in peritubular capillaries is higher in LN in response to inflammatory cytokines. The discrepancy between the levels of vascular expression of ANXA2 vs S100A10 might be due to the reactivity of the anti-ANXA2 antibody used in our study. In fact, the antibody might bind to monomeric and/or tetrameric ANXA2 subunits.

    Our present data suggest that the presence of vascular lesions (such as APSN and glomerular thrombosis) could modify ANXA2 vascular expression in LN. Daugas et al32 observed APSN in 32% of their patients with lupus glomerulopathy and observed that APSN was associated with renal morbidity. A study of a large cohort of patients with LN found that 17.6% had thrombotic microangiopathy.33 These patients had worse renal outcome than patients with other renal vascular lesions. ANXA2 could emerge as a novel marker of vascular renal lesions in LN. However, this study is limited by the small number of patients with lupus, particularly those with renal vascular lesions.

    In conclusion, our data show intense vascular expression of ANXA2 in LN, while expression of its subunit S100A10 is weaker. However, expression of S100A10 in peritubular capillaries is significantly greater in patients with lupus than in controls. The presence of vascular lesions such as glomerular microthrombosis and APSN appear to be associated with differences in expression of ANXA2 in peritubular capillaries. Further analysis of larger cohorts of patients with lupus undergoing kidney biopsy is needed to assess the value of ANXA2 and its S100A10 subunit as novel biomarkers of active LN in general and vascular lesions in LN in particular.

    Take home messages

    • Vascular expression of ANXA2 is increased in lupus nephritis (LN)

    • Vascular expression of its subunit S100A10 is weaker in LN

    • Expression of S100A10 in peritubular capillaries is significantly more intense in patients with LN than that observed in control subjects

    • Expression of ANXA2 in peritubular capillaries is significantly more intense in patients with LN with renal vascular lesions than in those without renal vascular lesions

    • Further studies are needed to assess the value of ANXA2 and its S100A10 subunit as novel biomarkers of active LN or of vascular lesions in LN

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    Supplementary materials

    • Abstract in French

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Handling editor Stephen Jolles

    • Contributors All authors are aware of and have agreed to this submission and have individually contributed to the work as described. Writing of paper: VS.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.