Abstract

Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SS^LepRmutant) rats was associated with increased macrophage inflammatory protein alpha (MIP3a) expression prior to puberty. Therefore, this study tested the hypothesis that MIP3α plays a role in recruiting immune cells, thereby triggering renal inflammation and early progressive renal injury in SS^LepRmutant rats prior to puberty. Four-week-old SS and SS^LepRmutant rats either served as control (IgG; i.p., every other day) or received MIP3a neutralizing antibody (MNA; 100 µg/kg) for 4 weeks. MNA reduced circulating and renal MIP3a levels and pro-inflammatory immune cells by 50%. While MNA treatment did not affect blood glucose and plasma cholesterol levels, MNA markedly decreased insulin resistance and triglyceride levels in SS^LepRmutant rats. We observed no differences in MAP between SS and SS^LepRmutant rats, and MNA had no effect on MAP in either strain. Proteinuria was significantly increased in SS^LepRmutant rats versus SS rats over the course of the study. Treatment with MNA markedly decreased proteinuria in SS^LepRmutant rats while not affecting SS rats. Also, MNA decreased glomerular and tubular injury and renal fibrosis in SS^LepRmutant rats while not affecting SS rats. Overall, these data indicate MIP3a plays an important role in renal inflammation during the early progression of renal injury in obese SS^LepRmutant rats prior to puberty. These data also suggest that MIP3a may be a novel therapeutic target to inhibit insulin resistance and prevent progressive proteinuria in obese children.

Significance Statement Childhood obesity is increasing at an alarming rate and is now being associated with renal disease. While most studies have focused on the mechanisms of renal injury associated with adult obesity, few studies have examined the mechanisms of renal injury involved during childhood obesity. In the current study, we observed that the progression of renal injury in obese SS^LepRmutant rats was associated with an increase in MIP3a, a chemokine, before puberty, and inhibition of MIP3a markedly reduced renal injury.