Anales de Nefrología
Número 78, 14 de Enero de 2010
Noticia adicional
FULLTEXT: -NEPHROLOGY & PROTEINURIA & IMMUNITY: -An Overstated Relationship?
It is the earliest sign of renal complications of diabetes, obesity, and the metabolic syndrome.
Therapy to reduce or prevent proteinuria is therefore highly desirable.
Several advances1,2,3,4,5 have helped to refine the targets for such therapy, and — as the recent study by Faul and colleagues1 shows — these advances have delivered some surprises.
Proteinuria occurs when the permeability of the glomerular capillary wall is increased. This increase may occur because of inflammatory injury in systemic autoimmune diseases such as lupus or small-vessel vasculitis.
In these situations, it is easy to understand why antiinflammatory agents such as corticosteroids, immune-modulating agents such as cyclosporine or cyclophosphamide, or both can be effective treatments.
However, the effectiveness of these drugs in the more common forms of proteinuric renal disease in which there is no inflammation, such as minimal-change nephropathy and focal segmental glomerulosclerosis, is more difficult to explain.
Since the drugs have been thought to act predominantly on cells of the immune system, nephrologists have traditionally invoked explanations of links between lymphocytes (and the soluble factors produced by them) and kidney injury.
However, direct evidence in support of these links has been lacking.
The study by Faul et al. addresses this anomaly by focusing on the podocyte, a key type of cell in the glomerular capillary wall that is believed to prevent proteinuria in healthy persons.
The podocyte's function depends on a complex and unique structure (Figure 1) that, in turn, depends on a tightly regulated actin cytoskeleton. The authors found that cyclosporine, the effectiveness of which has often been described as evidence of a key etiologic role for T lymphocytes in proteinuric diseases, has direct effects on the actin cytoskeleton (and therefore the shape) of podocytes.
The mechanism (Figure 2) involves synaptopodin, a key stabilizer of the actin cytoskeleton in podocytes. When synaptopodin is phosphorylated, it binds to another protein called 14-3-3 and is thus protected from degradation. Calcineurin, which is blocked by cyclosporine, dephosphorylates synaptopodin and allows its degradation. Faul et al. also found that increasing the level of degradation-resistant synaptopodin in podocytes protects against proteinuria and that expression of activated calcineurin in podocytes leads to proteinuria.
Figure 2. The Effect of Calcineurin on Synaptopodin.
Synaptopodin, when phosphorylated, binds to the 14-3-3 protein and is protected from degradation. Synaptopodin stabilizes the actin cytoskeleton, allowing the podocyte to maintain its shape (Panel A). Calcineurin dephosphorylates synaptopodin, which then separates from 14-3-3 and can be degraded by cathepsin L. Its stabilizing effect on the actin cytoskeleton is lost, and the cell loses its shape (Panel B). Cyclosporin inhibits the action of calcineurin, preventing dephosphorylation of synaptopodin and allowing its actin-stabilizing effect to continue (Panel C). P denotes phosphorylation.
Taken together, the findings provide support for the contention that the antiproteinuric effect of cyclosporine can be explained by its direct effects on podocytes, not by its actions on T lymphocytes. This explanation suggests that nephrologists have been using the right approach for the wrong reason, and it raises the tantalizing possibility that other proteinuric diseases — diabetic nephropathy being the most clinically important challenge — could also be treated by agents that stabilize the podocyte cytoskeleton. Clearly this notion will be of more practical value if selective agents can be developed; cyclosporine's complex effects include nephrotoxicity, so it would not appear to be a sensible choice for the treatment of diabetic nephropathy.
So, is the immune system involved in the induction of proteinuria at all? The most compelling evidence in support of this model is provided by the effectiveness of the selective anti–B-cell agent rituximab in proteinuric diseases.2 Nevertheless, the data described by Faul et al. strongly suggest a reassessment of whether agents targeting lymphocytes are the most logical choice, given that their effectiveness might be at least partially explained by direct effects on podocytes.
A similar suggestion has been made in recent years with respect to glucocorticosteroids in proteinuric diseases: studies from my group and others have shown that these drugs have direct effects on podocytes, including effects on their actin cytoskeletons.3,4 Grimbert and colleagues5 highlight the trend in thinking among nephrologists. They identified a protein called c-mip that affects the actin cytoskeleton in lymphocytes and is up-regulated in lymphocytes in patients with the nephrotic syndrome. They recently observed that the same protein is up-regulated in podocytes in proteinuric diseases; they also found that specific overexpression in podocytes leads to proteinuria (Sahali D: personal communication). The podocytes overexpressing c-mip had the same morphologic characteristics as those of human proteinuric diseases, with effacement of foot processes and loss of the cortical actin cytoskeleton. Regardless of whether c-mip is induced in both lymphocytes and podocytes by a common agent, the results indicate that it is the podocyte abnormality that should be targeted for therapy. Unsuspected similarities between the podocyte and lymphocyte may underlie what would now seem to be a misguided approach: the targeting of the immune system.
These studies collectively point to the podocyte as an attractive target and, in particular, the actin cytoskeleton — the stabilization of which informs the complex morphologic features on which podocyte function depends.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Academic Renal Unit, University of Bristol and Southmead Hospital — both in Bristol, United Kingdom.
References
- Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the anti-proteinuric effect of cyclosporine A. Nat Med 2008;14:931-938.
- Guigonis V, Dallocchio A, Baudouin V, et al. Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol 2008;23:1269-1279.
- Xing CY, Saleem MA, Coward RJ, Ni L, Witherden IR, Mathieson PW. Direct effects of dexamethasone on human podocytes. Kidney Int 2006;70:1038-1045. [CrossRef][ISI][Medline]
- Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE. Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 2005;68:2473-2483. [CrossRef][Medline]
- Grimbert P, Valanciute A, Audard V, et al. Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization. J Exp Med 2003;198:797-807. [Free Full Text]
NEJM.Vol. 359:2492-2494 Dec. 4, 2008 Number 23
Proteinuria and Immunity--An Overstated Relationship?
Peter W. Mathieson, Ph.D.
SEE FULLTEXT
