Administration of MIP3‐alpha neutralizing antibody reduces the renal infiltration of dendritic cells and Th17s and attenuates progressive proteinuria in obese Dahl salt‐sensitive rats

Abstract

Recently, we reported the early development of renal injury was associated with renal hyperfiltration along with increased renal macrophage infiltration and macrophage inflammatory protein alpha (MIP3α; inflammatory chemoattractant cytokine) expression in obese SSLepRmutant rats prior to puberty. MIP3α signals through the CCR6 receptor to recruit stimulatory dendritic cells (sDCs), which have been shown to play a pivotal role in cardiorenal injury by increasing pro-inflammatory T-helper 17 cells (Th17s). Therefore, the present study examined whether chronic blockade of MIP3α signaling would reduce the renal infiltration of sDCs and Th17s and slow the early progression of proteinuria in obese SSLepRmutant rats prior to puberty. Four-week-old SS and SSLepRmutant rats were separated into four groups (n=5/group): (1) SS and (2) SSLepRmutant rats treated with vehicle-PBS and (3) SS and (4) SSLepRmutant rats treated with MIP3α neutralizing antibody (MNA; 100 µg/kg, i.p., every other day) for 4 weeks. We found a significant increase in the infiltration of sDCs and Th17s in the kidneys from vehicle-SSLepRmutant rats compared to their lean vehicle-SS counterparts. Chronic treatment with MNA only significantly reduced renal sDCs and Th17s in SSLepRmutant rats. While treatment with MNA did not have an effect on blood glucose and plasma triglyceride and cholesterol levels, MNA markedly reduced plasma insulin levels in SSLepRmutant rats (9.7±2.3 vs. 3.5±0.7 ng/ml respectively; p<0.05). MAP was significantly higher in vehicle-SSLepRmutant rats compared to values measured in vehicle-SS rats (160±10 vs. 127±7 mmHg, respectively p<0.05). However, chronic treatment with MNA had no effect on MAP in the SSLepRmutant rats in comparison to the vehicle- SSLepRmutant rats (150±3 mmHg). At baseline, proteinuria was not markedly elevated in SSLepRmutant rats compared to SS rats (31±15 vs. 10±3 mg/day, respectively). However, proteinuria markedly increased in SSLepRmutant rats versus SS rats over the course of the study (446±54 vs. 51±16 mg/day, respectively; p<0.05). Chronic treatment with MNA significantly decreased proteinuria in SSLepRmutant rats (149±19 mg/day; p<0.05 vs. vehicle-SSLepRmutant rats) while not having any effect in SS rats (41±12 mg/day). Overall, these data indicate MIP3α plays a major role in the recruitment of sDCs and Th17s during the early progression of proteinuria in obese SSLepRmutant rats prior to puberty. These results also suggest that MIP3α may be a novel therapeutic target to inhibit insulin resistance and prevent progressive proteinuria in obese children.