title: 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.
abstract: Interferon (IFN)-α and IFN-β are the central regulators of antiviral immunity but little is known about their roles in viral glomerulonephritis (eg, HIV nephropathy). We hypothesized that IFN-α and IFN-β 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-β significantly induced podocyte death and increased the permeability of podocyte monolayers. In contrast, only IFN-α 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-α or IFN-β aggravated proteinuria, macrophage influx, and glomerulosclerosis. A detailed analysis showed that only IFN-β 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-α and IFN-β have both common and differential effects on podocytes and parietal epithelial cells, which together promote glomerulosclerosis by enhancing podocyte loss while suppressing podocyte regeneration from local progenitors.
authors.affiliation: Nephrological Center, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München-Ludwig Maximilian University, Campus Innenstadt, Munich, Germany.
authors.forename: Adriana
authors.initials: A
authors.lastname: Migliorini
authors.forename: Maria L
authors.initials: ML
authors.lastname: Angelotti
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.forename: Onkar O
authors.initials: OO
authors.lastname: Kulkarni
authors.forename: Jana
authors.initials: J
authors.lastname: Demleitner
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Costanza
authors.initials: C
authors.lastname: Sagrinati
authors.forename: Lara
authors.initials: L
authors.lastname: Ballerini
authors.forename: Anna
authors.initials: A
authors.lastname: Peired
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000503:physiopathology; D015658:HIV Infections / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D050199:Podocytes / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D016899:Interferon-beta; D004317:Doxorubicin