Background The pathogenesis of minimal change nephritic syndrome (MCNS), the commonest cause of NS in children, is unknown. Strong evidence exists suggesting that cytokines mediate proteinuria and NS. We have previously shown that IL-13 gene expression is upregulated in MCNS in relapse in CD4+ and CD8+ T-cells. However, IL-13's role in mediating disease is unclear. Here we aimed to investigate the effects of IL-13 on proteinuria, NS, and expression of podocyte-specific genes using an IL-13 gene expression model in the rat.
Methods The complete coding sequence of rat IL-13 was cloned into expression vector (pCI). Female Wistar rats received 200 μg IL13-pCI by electroporation every 10 d. Control rats received (pCI only). 24 hr protein excretion and serum IL-13 were measured by ELISA. Glomeruli were isolated and examined for B71, nephrin, podocin, (Dag1) and IL-13R expression using RT-PCR and immunofluorescence. Histology of kidneys was also examined.
Results The mean 24 hr urine protein in IL-13-pCI rats was significantly higher than controls. Compared to controls, IL-13-pCI rats showed lower mean serum albumin, hypercholesterolemia, and NS with edema. IL-13-pCI rats developing NS had the highest serum IL-13 levels. Glomeruli from IL-13-pCI rats showed 80% effacement of podocyte foot processes, with nephrotic rats showing the most pronounced pathology. Control rats showed no pathologic changes. Gene expression for IL-13R and subunits and B7-1 were upregulated in the IL-13-pCI rats while podocyte-specific genes (Dag1, podocin, and nephrin) were downregulated. Controls showed no changes.
Conclusions IL-13 overexpression results in podocyte injury with down-regulation of nephrin, podocin, and Dag1 and up-regulation of B7-1 resulting in the development of nephropathy characterized by albuminuria, hypoalbuminemia, hypercholesterolemia, and lesions similar to MCNS man. These data suggest that development of novel therapies directed at regulation of IL-13 gene expression may be useful in treatment of MCNS.
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