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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.