Chronic treatment with IL-25 increases renal M2 macrophages and reduces renal injury in obese Dahl salt-sensitive rats during the prepubescent stage.

Recently, we have reported that the early progression of proteinuria in the obese Dahl salt-sensitive (SS) leptin receptor mutant (SS^LepRmutant) strain was associated with increased renal macrophage infiltration before puberty. Macrophages can be divided into two distinct phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory). Moreover, previous studies have demonstrated that interleukin (IL)-25 converts resting macrophages and M1 into M2. Therefore, the present study examined whether treatment with IL-25 would reduce the early progression of renal injury in SS^LepRmutant rats by increasing renal M2. We also investigated the impact of IL-25 on M2 subtypes: M2a (wound healing/anti-inflammatory), M2b (immune mediated/proinflammatory), M2c (regulatory/anti-inflammatory), and M2d (tumor associated/proangiogenic). Four-wk-old SS and SS^LepRmutant rats were treated with either control (IgG) or IL-25 (1 µg/day ip every other day) for 4 wk. The kidneys from SS^LepRmutant rats displayed progressive proteinuria and renal histopathology versus SS rats. IL-25 treatment had no effect on these parameters in SS rats. However, in the SS^LepRmutant strain, proteinuria was markedly reduced after IL-25 treatment. Chronic treatment with IL-25 significantly decreased glomerular and tubular injury and renal fibrosis in the SS^LepRmutant strain. Although the administration of IL-25 did not change total renal macrophage infiltration in both SS and SS^LepRmutant rats, IL-25 increased M2a by >50% and reduced M1 by 60% in the kidneys of SS^LepRmutant rats. Overall, these data indicate that IL-25 reduces the early progression of renal injury in SS^LepRmutant rats by inducing M2a and suppressing M1 and suggest that IL-25 may be a therapeutic target for renal disease associated with obesity. NEW & NOTEWORTHY For the past few decades, immune cells and inflammatory cytokines have been demonstrated to play an important role in the development of renal disease. The present study provides strong evidence that interleukin-25 slows the early progression of renal injury in obese Dahl salt-sensitive rats before puberty by increasing systemic anti-inflammatory cytokines and renal M2a macrophages.