IFN-αand IFN-β Specifically Affect Renal Progenitors and Podocytes In-Vitro and In-Vivo

Background: Viral infections can be associated with glomerulonephritis in various ways which is likely to involve antiviral immunity. IFNα and IFNβ orchestrate antiviral defence and potentially contribute to GN. For example, lack of the IFNα-R ameliorates murine immune complex disease complicated by glomerulonephritis but local effects of IFNα/β on glomerular pathology remain speculative. Methods: C133+CD24+ human renal progenitors and podocytes cultured +/- hIFNα and hIFNβ. SCID mice injected with adriamycin +/- recombinant mIFNα and mIFNβ. Results: IFNα and IFNβ both activated renal progenitors to express several interferonrelated (antiviral) genes such as MX1, IFIT1 and CXCL10. IFN-α significantly decreased the proliferation of human renal progenitors, by contrast IFNβ inhibited differentiation of renal progenitors towards podocytes as determined by induced nephrin expression. Next we compared the impact of recombinant IFNα and IFNβ injections on adriamycininduced nephropathy in SCID mice which allowed us to exclude IFN-dependent effects on adaptive immunity. Both IFNs increased proteinuria as compared to control mice injected with adriamycin only. Quantitative morphometry by confocal microscopy revealed that IFNβ injections had specifically reduced the number of WT1+/nephrin+ podocytes while IFNα injections specifically reduced the numbers of proliferating parietal epithelial cells, respectively. In summary, both type I IFNs can aggravate glomerular pathology, albeit in different ways. IFNα impairs the proliferation of potential podocyte progenitors, while IFNβ mostly impairs progenitor differentiation in vitro. Conclusions: These data propose that IFNα and IFNβ contribute to glomerulosclerosis and proteinuria by specifically affecting homeostasis of podocytes and their potential repair by local progenitors, a mechanism that may contribute to in viral infection-associated glomerular pathology.