IL‐25 reduces early progression of renal injury in obese Dahl salt‐sensitive rats via inducing renal M2a‐macrophages and suppressing M1‐macrophages

Abstract

Recently, we reported that the early progression of proteinuria in the obese Dahl salt-sensitive (SSLepRmutant) strain was associated with increased renal macrophage infiltration in the absence of hyperglycemia and elevations in arterial pressure. Macrophages (CD68+) can be divided into two distinct phenotypes: M1-macrophages (pro-inflammatory; CD68+/iNOS+), and M2-macrophages (anti-inflammatory; CD68+/CD163+). M1-macrophages induce renal inflammation and fibrosis, whereas M2-macrophages reduce renal inflammation and fibrosis. Moreover, previous studies have demonstrated that interlukin-25 (IL-25) converts resting macrophages and M1-macrophages into M2-macrophagess. Therefore, the objective of the current study was to examine whether treatment with IL-25 would reduce the early progression of renal injury in SSLepRmutant rats by increasing renal M2-macrophages. We also investigated the impact of IL-25 on M2-macrophage subtypes: M2a (wound healing/anti-inflammatory; CD68+/CD163+/TLR1-), M2b (immune mediated/pro-inflammatory; CD68+/iNOS-/CD86+), M2c (Regulatory/anti-inflammatory; CD68+/CD163+/TLR1+), and M2d (tumor associated macrophage/pro-angiogenic; CD68+/VEGF+). Four week-old SSWT and SSLepRmutant rats were treated with either vehicle (PBS) or IL-25 (1µg/day, i.p., every other day) for 4 weeks. While the administration of IL-25 did not change total renal macrophage infiltration in both SSWT and SSLepRmutant rats, IL-25 increased M2a-macrophages by >50% and reduced M1-macrophage by 60% in the kidneys of SSLepRmutant rats. Interestingly, IL-25 significantly increased the insulin sensitivity without changing plasma glucose, triglyceride and total cholesterol levels in SSLepRmutant rats. IL-25 administration had no effect on the progression of proteinuria or renal histopathology in SSWT rats. However, in the SSLepRmutant strain, proteinuria was markedly reduced during the first 2 weeks of treatment (105±13 vs. 295±45 mg/day, respectively), which was further consistent after 4 weeks of treatment (314±57 vs. 467±55 mg/day, respectively). The kidneys from SSLepRmutant rats displayed glomerular injury with increased mesangial expansion and renal fibrosis versus SSWT rats. Chronic treatment with IL-25 significantly decreased glomerular injury and renal fibrosis in the SSLepRmutant strain. Overall, these data indicate that IL-25 reduces the early progression of renal injury in SSLepRmutant rats by inducing M2a-macrophages and suppressing M1-macrophages. Therefore, IL-25 may be considered a therapeutic target for renal disease associated with obesity.