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Editorials |
: A Novel Way to Treat Nephrotic Syndrome?Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
Correspondence: Professor Andy Rees, Institute of Clinical Pathology, Medical University of Vienna, Währinger Gürtel 18-20, A-1080 Vienna, Austria. Phone:+43-1-4040-03186; Fax: +43-1-4040-05193; E-mail: andrew.rees{at}mediuniwien.ac.at
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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 anti-inflammatory 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-Faslpr 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 endothelia, and human umbilical vein endothelia. These studies documented similar effects on electrical resistance and albumin permeability to those with glomerular endothelia and demonstrated that these changes correlate with increased expression of junctional proteins, including occludin and platelet-endothelial cell adhesion molecule-1.6–9 In contrast, 
-IFN, TNF-
, and LPS all have the opposite effect on electrical resistance, permeability, and expression of junctional proteins10; however, responses to proinflammatory cytokines are markedly attenuated (and in some cases abrogated) by simultaneous incubation with IFN-1a. These inhibitory effects on brain endothelia are thought to be critical for the therapeutic effect of IFN-1a in multiple sclerosis.
Endothelia differ markedly between structure and function, so there are dangers of extrapolating results using cells from one vascular territory to another. This is especially so when comparing brain or retinal endothelia with those from the glomerulus. The one is responsible for the blood-brain/blood-retinal barrier and consequently is especially impermeable to proteins, has an electrical resistance that is five times higher than glomerular endothelia, and lacks fenestrae. In contrast, glomerular endothelia are highly permeable and have numerous fenestrae that may be important for the glomerular permeability barrier; however, the cells used by Satchell et al. will also have had relatively few fenestrae because these become abundant only in cultured glomerular endothelium after exposure to vascular endothelial growth factor (VEGF), which was not used here.11 This merely emphasizes the need for further work to define the exactly how IFN-1a interacts with glomerular endothelia and in particular on fully fenestrated glomerular endothelial cells. Exploration of the interactions with VEGF will be particularly interesting, not least because VEGF inhibitors used clinically can induce proteinuria,12 as will comparisons with the effects of angiopoietin-1 and increased intracellular cAMP, both of which decrease glomerular endothelial cell permeability in vitro.11
The marked reduction of IFN-1a on proteinuria also raises questions about he nature of the glomerular permeability barrier and the way it is compromised in disease. Until recently, there was a broad consensus that the podocyte slit diaphragm provided the principal barrier to proteins, but there is clear evidence that both the glomerular basement membrane13 and glomerular endothelial cells are also important, although much remains controversial, especially concerning endothelium, as recently debated in JASN.14 In these studies, it is interesting that the rate of passage of FITC-BSA through glomerular endothelial cells was less than half that through podocytes, although possibly a simple in vitro artifact of the experimental conditions. The lack of fenestrae would provide an obvious explanation except that Satchell previously reported11 that permeability to FITC-BSA did not change when fenestrae were induced by VEGF, although electrical resistance decreased rapidly.
There remains the most important question of all: Can the strikingly specific effect of IFN-1a on proteinuria be applied clinically in patients with nephrotic syndrome? As the authors point out, IFN- treatment in hepatitis C has been associated with reduced proteinuria in some patients in whom it is complicated by membranoproliferative glomerulonephritis.15 Whether due to IFN-'s antiviral properties, as was assumed, or a renal effect cannot be discerned without much closer definition between the start of treatment and reduction of proteinuria. Again, the report of Satchell et al. should provoke food for thought and much, much more work.
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See related article, "Interferon- Reduces Proteinuria in Experimental Glomerulonephritis," on pages 2875–2884.
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Related Article
Reduces Proteinuria in Experimental Glomerulonephritis
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