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Abstract
BackgroundIgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Circulating galactose-deficient IgA (gd-IgA), present in patients with IgAN, form immune complex deposits in the glomerular mesangium causing local proliferation and matrix expansion. Intriguing though, individuals having gd-IgA deposits in the kidneys do not necessarily have signs of glomerular disease. Recurrence of IgAN only occurs in less than half of transplanted patients with IgAN, indicating that gd-IgA is not the only factor driving the disease. We hypothesize that, in addition to IgA complexes, patients with IgAN possess a subtype of mesangial cells highly susceptible to gd-IgA induced cell proliferation.MethodsTo test the hypothesis, we designed a technique to culture primary mesangial cells from renal biopsies obtained from IgAN patients and controls. The cell response to gd-IgA treatment was then measured both on gene and protein level and the proliferation rate of the cells in response to PDGF was investigated.ResultsWhen treated with gd-IgA, mesangial cells from patients with IgAN express and release more PDGF compared to controls. In addition, the mesangial cells from patients with IgAN were more responsive to treatment with PDGF resulting in an increased proliferation rate of the cells compared to control. Mesangial cells cultured from patients with IgAN expressed and released more IL-6 than controls and had a higher expression of matrix genes. Both mesangial cells derived from patients with IgAN and controls increased their expressed TGFβ1 and CCL5 when treated with gd-IgA.ConclusionWe conclude that mesangial cells derived from IgAN patients have a mesangioproliferative phenotype with increased reactivity to IgA and that these cellular intrinsic properties may be important for the development of IgA nephropathy.
Highlights
IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people
Expression and increased sensitivity to PDGF IgAN patients have shown increased PDGFB expression [7] and we thereby investigated if PDGFB expression was altered in IgAN Mesangial cells (MCs) following stimulation with gdIgA
We found that a 6 h stimulation with galactose-deficient IgA (gd-IgA) significantly increased the gene expression of PDGFB compared to untreated IgAN MCs, see Fig. 2a
Summary
IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Ebefors et al BMC Nephrology (2016) 17:40 increase of PDGFB in patients with IgAN [7], and stimulation of mesangial cells in vitro with PDGF increases their expression of several cytokines and growth factors such as IL-6 and TGFβ1 [8]. [16,17,18,19] the clinical disease recurs in less than half (22–33 %) of the transplanted patients [20,21,22] Based on these facts, we wanted to investigate the role of the mesangial cells in development of IgAN. We were able to demonstrate that mesangial cells from patients with IgAN are significantly more reactive to IgA1 and PDGF stimulation and the cells express and produce higher levels of certain growth factors, cytokines and matrix components
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