title: Synergistic effect of mesangial cell-induced CXCL1 and TGF-β1 in promoting podocyte loss in IgA nephropathy.
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.
authors.affiliation: Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China ; Peking University Institute of Nephrology, Beijing, China ; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China ; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Qingxian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sufang
authors.initials: S
authors.lastname: Shi
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.forename: Jicheng
authors.initials: J
authors.lastname: Lv
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism* / Q000652:urine; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D005922:Glomerulonephritis, IGA / Q000378:metabolism* / Q000473:pathology* / Q000652:urine; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000652:urine; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D017077:Culture Media, Conditioned; D007070:Immunoglobulin A; D023063:Receptors, Interleukin-8B; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
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