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Recently, we reported that the early progression of proteinuria in the obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain was associated with increased renal macrophage infiltration prior to puberty. Macrophages can be divided into two distinct phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory). Moreover, previous studies have demonstrated that interlukin-25 (IL-25) converts resting macrophages and M1 into M2. Therefore, the current study examined whether treatment with IL-25 would reduce the early progression of renal injury in SSLepRmutant rats by increasing renal M2. We also investigated the impact of IL-25 on M2 subtypes: M2a (wound healing/anti-inflammatory), M2b (immune mediated/pro-inflammatory), M2c (regulatory/anti-inflammatory), and M2d (tumor associated/pro-angiogenic). Four-week-old SS and SSLepRmutant rats were treated with either control (IgG) or IL-25 (1µg/day, i.p., every other day) for 4 weeks. The kidneys from SSLepRmutant 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 SSLepRmutant 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 SSLepRmutant strain. While the administration of IL-25 did not change total renal macrophage infiltration in both SS and SSLepRmutant rats, IL-25 increased M2a by >50% and reduced M1 by 60% in the kidneys of SSLepRmutant rats. Overall, these data indicate that IL-25 reduces the early progression of renal injury in SSLepRmutant rats by inducing M2a and suppressing M1 and suggest that the IL-25 may be a therapeutic target for renal disease associated with obesity.

Recently, we reported that obese Dahl salt-sensitive (SS) leptin receptor mutant (SSLepRmutant) rats display progressive renal injury. The present study demonstrated that the early development of renal injury in the SSLepRmutant strain is associated with an increase in the renal infiltration of macrophages compared with lean SS rats. We also examined whether depletion of macrophages with clodronate would reduce the early progression of renal injury in the SSLepRmutant strain. Four-week-old SS and SSLepRmutant rats were treated with either vehicle (PBS) or clodronate (50 mg/kg ip, 2 times/wk) for 4 wk. While the administration of clodronate did not reduce renal macrophage infiltration in SS rats, clodronate decreased macrophages in the kidneys of SSLepRmutant rats by >50%. Interestingly, clodronate significantly reduced plasma glucose, insulin, and triglyceride levels and markedly improved glucose tolerance in SSLepRmutant rats. Treatment with clodronate had no effect on the progression of proteinuria or renal histopathology in SS rats. In the SSLepRmutant strain, proteinuria was markedly reduced during the first 2 wk of treatment (159 ± 32 vs. 303 ± 52 mg/day, respectively). However, after 4 wk of treatment, the effect of clodronate was no longer observed in the SSLepRmutant strain (346 ± 195 vs. 399 ± 50 mg/day, respectively). The kidneys from SSLepRmutant rats displayed glomerular injury with increased mesangial expansion and renal fibrosis versus SS rats. Treatment with clodronate significantly decreased glomerular injury and renal fibrosis in the SSLepRmutant strain. Overall, these data indicate that the depletion of macrophages improves metabolic disease and slows the early progression of renal injury in SSLepRmutant rats.

Diabetes and hypertension are the major causes of chronic kidney disease (CKD). Epidemiological studies within the last few decades have revealed that obesity-associated renal disease is an emerging epidemic and that the increasing prevalence of obesity parallels the increased rate of CKD. This has led to the inclusion of obesity as an independent risk factor for CKD. A major complication when studying the relationship between obesity and renal injury is that cardiovascular and metabolic disorders that may result from obesity including hyperglycemia, hypertension, and dyslipidemia, or the cluster of these disorders [defined as the metabolic syndrome, (MetS)] also contribute to the development and progression of renal disease. The associations between hyperglycemia and hypertension with renal disease have been reported extensively in patients suffering from obesity. Currently, there are several obese rodent models (high-fat diet-induced obesity and leptin signaling dysfunction) that exhibit characteristics of MetS. However, the available obese rodent models currently have not been used to investigate the impact of obesity alone on the development of renal injury before hypertension and/or hyperglycemia. Therefore, the aim of this review is to describe the incidence and severity of renal disease in these rodent models of obesity and determine which models are suitable to study the independent effects obesity on the development and progression of renal disease.