The Antiviral Cytokines IFN-α and IFN-β Modulate Parietal Epithelial Cells and Promote Podocyte Loss Implications for IFN Toxicity, Viral Glomerulonephritis, and Glomerular Regeneration
The Antiviral Cytokines IFN-α and IFN-β Modulate Parietal Epithelial Cells and Promote Podocyte Loss Implications for IFN Toxicity, Viral Glomerulonephritis, and Glomerular Regeneration
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DOI：
10.1016/j.ajpath.2013.04.017
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发表时间：
2013-08-01
影响因子：
6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Migliorini, Adriana;Angelotti, Maria L.;Anders, Hans-Joachim
干扰素（IFN）-α和IFN-β是抗病毒免疫的中心调节因子，但对它们在病毒性肾小球肾炎（如HIV肾病）中的作用知之甚少。我们假设IFN-α和IFN-β会引发局部炎症和足细胞丢失。我们发现，这两种干扰素始终激活人类和小鼠足细胞和壁上皮细胞表达许多干扰素刺激的基因。然而，只有IFN-β显著诱导足细胞死亡，并增加足细胞单层的渗透性。相反，只有IFN-α引起细胞周期停滞，抑制壁上皮细胞的迁移。两种IFN均抑制肾祖细胞分化为成熟足细胞。在阿霉素肾病中，注射IFN-α或IFN-β可加重蛋白尿、巨噬细胞内流和肾小球硬化。详细的分析表明，只有IFN-β诱导足细胞有丝分裂。然而，这并不导致增殖，而是与通过足细胞脱离和/或有丝分裂足细胞死亡（有丝分裂灾难）引起的足细胞损失相关。我们没有检测到TUNEL阳性足细胞。因此，IFN-α和IFN-β对足细胞和壁上皮细胞具有共同和不同的作用，它们通过增强足细胞损失同时抑制足细胞从局部祖细胞再生来共同促进肾小球硬化。
Interferon (IFN)-alpha and IFN-beta are the central regulators of antiviral immunity but little is known about their roles in viral glomerulonephritis (eg, HIV nephropathy). We hypothesized that IFN-alpha and IFN-beta would trigger local inflammation and podocyte Loss. We found that both IFNs consistently activated human and mouse podocytes and parietal epithelial cells to express numerous IFN-stimulated genes. However, only IFN-beta significantly induced podocyte death and increased the permeability of podocyte monolayers. In contrast, only IFN-alpha caused cell-cycle arrest and inhibited the migration of parietal epithelial cells. Both IFNs suppressed renal progenitor differentiation into mature podocytes. In Adriamycin nephropathy, injections with either IFN-alpha or IFN-beta aggravated proteinuria, macrophage influx, and glomerulosclerosis. A detailed analysis showed that only IFN-beta induced podocyte mitosis. This did not, however, lead to proliferation, but was associated with podocyte Loss via podocyte detachment and/or mitotic podocyte death (mitotic catastrophe). We did not detect TUNEL-positive podocytes. Thus, IFN-alpha and IFN-beta have both common and differential effects on podocytes and parietal epithelial cells, which together promote glomerulosderosis by enhancing podocyte loss while suppressing podocyte regeneration from local progenitors.