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

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.

Treatment With Lisinopril Prevents the Early Progression of Glomerular Injury in Obese Dahl Salt-Sensitive Rats Independent of Lowering Arterial Pressure.

Recently, we reported that obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) rats develop glomerular injury and progressive proteinuria prior to puberty. Moreover, this early progression of proteinuria was associated with elevations in GFR. Therefore, the current study examined whether treatment with lisinopril to reduce GFR slows the early progression of proteinuria in SSLepRmutant rats prior to puberty. Experiments were performed on 4-week-old SS and SSLepRmutant rats that were either treated with vehicle or lisinopril (20 mg/kg/day, drinking water) for 4 weeks. We did not observe any differences in MAP between SS and SSLepRmutant rats treated with vehicle (148 ± 5 vs. 163 ± 6 mmHg, respectively). Interestingly, chronic treatment with lisinopril markedly reduced MAP in SS rats (111 ± 3 mmHg) but had no effect on MAP in SSLepRmutant rats (155 ± 4 mmHg). Treatment with lisinopril significantly reduced proteinuria in SS and SSLepRmutant rats compared to their vehicle counterparts (19 ± 5 and 258 ± 34 vs. 71 ± 12 and 498 ± 66 mg/day, respectively). Additionally, nephrin excretion was significantly elevated in SSLepRmutant rats versus SS rats, and lisinopril reduced nephrin excretion in both strains. GFR was significantly elevated in SSLepRmutant rats compared to SS rats, and lisinopril treatment reduced GFR in SSLepRmutant rats by 30%. The kidneys from SSLepRmutant rats displayed glomerular injury with increased mesangial expansion and renal inflammation versus SS rats. Chronic treatment with lisinopril significantly decreased glomerular injury and renal inflammation in the SSLepRmutant rats. Overall, these data indicate that inhibiting renal hyperfiltration associated with obesity is beneficial in slowing the early development of glomerular injury and renal inflammation.