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

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.