Abstract 42: Inhibiting Stimulatory Dendritic Cells Reduces Early Progressive Proteinuria In Obese Dahl Salt-sensitive Rats.

Abstract

Childhood/prepubertal (PPO) obesity has emerged as an epidemic and major health problem over the last few decades and is a risk factor for the development of proteinuria. With the rising prevalence of obesity in children, studies examining how obesity contributes to the early development of proteinuria and renal injury in children are lacking. Recently, we observed that the early progression of proteinuria in the obese SS LepR mutant rats was associated with the increased renal infiltration of stimulatory dendritic cells (sDCs). Previous studies have demonstrated that sDCs interact with and activate T-cells to elicit a pro-inflammatory response. Therefore, the current study examined whether chronic treatment with abatacept will reduce proteinuria in SS LepR mutant rats prior to puberty by interfering with sDC-T-cell crosstalk. Four-week-old SS and SS LepR mutant rats were treated with either vehicle (PBS) or abatacept (1 mg/kg, i.p. every alternate day) for 4 weeks. We observed no significant differences in blood glucose levels and mean arterial pressure between vehicle- and abatacept-treated SS and SS LepR mutant rats. While proteinuria only rose from 9±3 to 48±28 mg/day in SS rats, proteinuria markedly increased from 40±13 to 638±73 mg/day in SS LepR mutant rats. Chronic treatment with abatacept significantly decreased the progression of proteinuria by almost 50% in SS LepR mutant rats (350±15 mg/day; p<0.05 vs. vehicle-treated SS LepR mutant rats) without having any effect in SS rats (29±11 mg/day). We observed a significant increase in the renal infiltration of sDCs and cytotoxic T-cells in SS LepR mutant rats in comparison to their lean SS counterparts, and chronic treatment with abatacept reduced the infiltration of sDCs and cytotoxic T-cells only in the SS LepR mutant rats. These data indicate that targeting sDC/T-cell interaction pathways could offer novel therapeutic insights in the early management of proteinuria and renal injury associated with PPO.