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.
PLoS One. 2013 Aug 30;8(8):e73425. doi: 10.1371/journal.pone.0073425. eCollection 2013.
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.
已有研究报道，足细胞丢失与 IgA 肾病（IgAN）的疾病严重程度和进展相关。然而，其在 IgAN 中的作用机制尚不清楚。最近的证据表明，来自 IgAN 患者的 IgA1 复合物可激活系膜细胞，诱导可溶性介质排泄，并通过系膜-足细胞的串扰进一步损伤足细胞。在本研究中，我们探讨了 IgAN 中系膜细胞诱导足细胞丢失的潜在机制。我们发现，与健康对照组相比，来自 IgAN 患者的 IgA1 复合物可显著上调系膜细胞中 CXCL1 和 TGF-β1 的表达。IgAN 患者的尿中 CXCL1 和 TGF-β1 水平也显著高于健康对照组。此外，尿中 CXCL1 和 TGF-β1 水平较高的 IgAN 患者表现出严重的临床和病理表现，包括 24 小时尿蛋白排泄量较高、eGFR 较低和新月体肾小球比例较高。进一步的体外实验表明，系膜细胞条件培养基（来自 IgAN 的 IgAN-HMCM）、rhCXCL1 与 rhTGF-β1 共同诱导足细胞死亡增加和足细胞黏附减少。此外，IgAN-HMCM 和 rhTGF-β1 可诱导足细胞过表达 CXCL1 的受体 CXCR2，但 rhCXCL1 则不能。此外，IgAN-HMCM 和 rhCXCL1 与 rhTGF-β1 诱导的足细胞死亡增加和黏附减少的作用可部分被 CXCR2 阻断抗体所挽救。此外，我们观察到 IgAN 患者尿液脱落的足细胞中表达 CXCR2。本研究表明，来自 IgAN 患者的 IgA1 复合物可上调系膜细胞中 CXCL1 和 TGF-β1 的分泌。此外，CXCL1 和 TGF-β1 的协同作用通过 CXCR2 进一步诱导足细胞死亡和黏附功能障碍。这可能是 IgAN 中观察到的足细胞丢失的潜在机制。
