FP210
THERAPEUTIC EFFECT OF siRNA-CD40 ON KIDNEY DAMAGE AFTER REVERSIBLE OBSTRUCTIVE NEPHROPATHY IN MICE

INTRODUCTION AND AIMS: The costimulatory CD40 pathway plays a role in inflammation. We have previously reported that renal CD40 was upregulated in a murine model of obstructive nephropathy. Here we sought to evaluate whether the administration of siRNA anti-CD40 has a therapeutic effect in a reversible UUO mice model (rUUO).

METHODS: Eight week-old C57BL6J male mice were divided into three groups: wild type (n=6); rUUO-Sham, animals with Saline Buffer (n=8) and rUUO+siRNA anti-CD40, animals with siRNA anti-CD40 (n=8). Ureteral clamping was performed on 8 week-old C57BL6J male mice. At day 3 after surgery, the ureteral clamp was removed and nephrectomy of the contralateral kidney was performed. Immediately siRNA anti-CD40 (50µg) was administrated via the tail vein. Mice were killed 48h hours after the siRNA or saline administration (day 5). Blood samples at days 0, 3, 4 and 5 were collected for creatinine analysis. Histology and kidney mRNA expression (CD40, iNOS, IL-2 and TGF-β1) were performed.

RESULTS: The administration of siRNA anti-CD40 was associated with a significant reduction of renal CD40 mRNA expression (Table). siRNA anti-CD40 reduced significantly the severity of acute renal failure associated with UUO as demonstrated by serum creatinine (Figure), lower tubular dilation and reduced cellular infiltrate (Table). These findings were in line with kidney mRNA gene expression, showing significantly lower levels of pro-inflammatory cytokines such as CD40, IL-2 and iNOS. Moreover, siRNA anti-CD40 was associated with the reduction of pro-fibrotic TGFβ-1 mRNA expression.

CONCLUSIONS: siRNA anti-CD40 has a therapeutic effect on the acute renal failure induced by restrictive uropathy. This strategy seems suitable to be tested in humans.

Open in new tabDownload slide