Synergistic effect of mesangial cell-induced CXCL1 and TGF-β1 in promoting podocyte loss in IgA nephropathy

PLoS One. 2013 Aug 30;8(8):e73425. doi: 10.1371/journal.pone.0073425. eCollection 2013.

Abstract

Podocyte loss has been reported to relate to disease severity and progression in IgA nephropathy (IgAN). However, the underlying mechanism for its role in IgAN remain unclear. Recent evidence has shown that IgA1 complexes from patients with IgAN could activate mesangial cells to induce soluble mediator excretion, and further injure podocytes through mesangial-podocytic cross-talk. In the present study, we explored the underlying mechanism of mesangial cell-induced podocyte loss in IgAN. We found that IgA1 complexes from IgAN patients significantly up-regulated the expression of CXCL1 and TGF-β1 in mesangial cells compared with healthy controls. Significantly higher urinary levels of CXCL1 and TGF-β1 were also observed in patients with IgAN compared to healthy controls. Moreover, IgAN patients with higher urinary CXCL1 and TGF-β1 presented with severe clinical and pathological manifestations, including higher 24-hour urine protein excretion, lower eGFR and higher cresentic glomeruli proportion. Further in vitro experiments showed that increased podocyte death and reduced podocyte adhesion were induced by mesangial cell conditional medium from IgAN (IgAN-HMCM), as well as rhCXCL1 together with rhTGF-β1. In addition, the over-expression of CXCR2, the receptor for CXCL1, by podocytes was induced by IgAN-HMCM and rhTGF-β1, but not by rhCXCL1. Furthermore, the effect of increased podocyte death and reduced podocyte adhesion induced by IgAN-HMCM and rhCXCL1 and rhTGF-β1 was rescued partially by a blocking antibody against CXCR2. Moreover, we observed the expression of CXCR2 in urine exfoliated podocytes in IgAN patients. Our present study implied that IgA1 complexes from IgAN patients could up-regulate the secretion of CXCL1 and TGF-β1 in mesangial cells. Additionally, the synergistic effect of CXCL1 and TGF-β1 further induced podocyte death and adhesion dysfunction in podocytes via CXCR2. This might be a potential mechanism for podocyte loss observed in IgAN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects
  • Cell Death / drug effects
  • Cells, Cultured
  • Chemokine CXCL1 / metabolism*
  • Chemokine CXCL1 / urine
  • Culture Media, Conditioned / pharmacology
  • Female
  • Fluorescent Antibody Technique
  • Glomerulonephritis, IGA / metabolism*
  • Glomerulonephritis, IGA / pathology*
  • Glomerulonephritis, IGA / urine
  • Humans
  • Immunoglobulin A / metabolism
  • Male
  • Mesangial Cells / metabolism*
  • Mesangial Cells / pathology
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Podocytes / pathology*
  • Receptors, Interleukin-8B / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / urine
  • Up-Regulation / drug effects

Substances

  • CXCL1 protein, human
  • Chemokine CXCL1
  • Culture Media, Conditioned
  • Immunoglobulin A
  • Receptors, Interleukin-8B
  • TGFB1 protein, human
  • Transforming Growth Factor beta1

Grant support

This work was supported by the National Science Foundation for Youths of China (Grant No. 81000297); the Major State Basic Research Development Program of China (973 program, No.2012CB517700); the National Natural Science Foundation for Innovative Research Groups of China (Grant No. 81021004); and the Beijing Natural Science Foundation (Grant No. 7131016). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.