Interferon-β

Abstract

Experimental studies to test the latest cytokine (or antibodies to it) in models of glomerular injury appear on an almost industrial scale. Most show modest benefits without providing serious mechanistic insights or the confidence that they will ever become clinical therapies. The article by Satchell et al. 1 in this issue of JASN describing the effect of IFN-␤1a in models of glomerulonephritis is different for at least three reasons: (1) It identifies a potential renal use for a cytokine already commonly applied in the clinic for other diseases; (2) it documents a striking reduction in proteinuria; and (3) it includes in vitro studies with glomerular endothelial cells and podocytes that not only provide a possible explanation for the in vivo results but also raise questions about the nature of the glomerular filtration barrier.Type 1 interferons, such as IFN-␤1a, are unusual in that they have well-documented immunosuppressive and antiinflammatory properties as well as inhibitory effects on fibroblast proliferation and scarring. 2 Type 1 IFN are an established treatment for chronic relapsing multiple sclerosis and for hepatitis C infection. 3,4 More recently, IFN-␤1a was shown to attenuate lupus nephritis in MRF-Fas lpr mice. 5 This provided a reasonable, if unadventurous, justification for examining the effects of IFN-␤1a on the evolution of nephrotoxic nephritis in WKY rats, a robust model of acute inflammation and progressive renal scarring. The results were both clear-cut and surprising: IFN-␤1a had no effect on the acute glomerular inflammation, progressive renal scarring, or the development of renal failure, but despite this, proteinuria was reduced by nearly 75% even when treatment was started after the onset of disease. The specific effect of IFN-␤1a on proteinuria was confirmed in two other models: Thy1.1 nephritis, in which it was equally effective, and puromycin nephropathy, in which it was even more so and decreased proteinuria by 97%.Uniquely, these studies dissociate a marked reduction of proteinuria from all other aspects of renal injury in these or, indeed, other rodent models of glomerular injury. Although unable to test directly whether IFN-␤1a influenced glomerular permeability, Satchell et al. tested its effect on cultured human glomerular endothelial cells and conditionally immortalized a human podocyte cell line. They found that IFN␤1a increased electrical resistance across the cultures (a surrogate marker for permeability for fluids and solutes) and decreased their permeability to BSA. This in turn led them to propose that IFN-␤1a reduces proteinuria through a direct effect on the glomerular filtration barrier mediated through effects on glomerular endothelium and/or podocytes. This of course needs to be proved.These studies did not address the issue of how IFN-␤1a reduced permeability glomerular endothelium and podocytes; however, there are clues from numerous previous studies on other types of vascular endothelium, including brain and retinal microvascular endothelia, bovine aortic end...