Abatacept decreases renal T-cell infiltration and renal inflammation and ameliorates progressive renal injury in obese Dahl salt-sensitive rats before puberty

Abstract

Abstract: Prepubertal obesity (PPO) is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) rats was associated with increased T-cell infiltration and activation prior to puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SSLepRmutant rats before puberty. Four-week-old SS and SSLepRmutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T-cells by almost 50% in SSLepRmutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha (MIP-3α) while increasing IL-4 in SSLepRmutant rats without affecting SS rats. While not having an impact on blood glucose, abatacept reduced hyperinsulinemia and plasma triglycerides in SSLepRmutant rats without affecting SS rats. We did not observe any differences in MAP among the groups. Proteinuria was markedly higher in SSLepRmutant rats versus SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SSLepRmutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SSLepRmutant rats vs SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SSLepRmutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with PPO.