Abstract 451: Depletion of Macrophage Prevents Exacerbated Renal Injury and Hypertension Induced by Degeneration of Trpv1-positive Nerves in Rats Subjected to Renal Ischemic Reperfusion and Salt Load

Abstract

High salt intake after recovery from renal ischemia-reperfusion (I/R) injury leads to hypertension and renal inflammation. This study tests the hypothesis that degeneration of transient receptor potential vanilloid type 1 (TRPV1)-positive nerves exacerbates salt-induced hypertension and renal inflammation after I/R via enhancing renal macrophage infiltration. Rats were fed a low sodium (0.4%) diet for 5 weeks after capsaicin pre-treatment (CAP, 100 mg/kg, s.c.) and renal I/R, followed by macrophage depletion with clodronate liposome (LC, 1.3 ml/kg/wk, i.v.) combined with a high sodium (4%) diet for 4 weeks. Western blot showed that CAP pretreatment further decreased renal TRPV1 levels after I/R (P<0.05), which was not affected by LC treatment. Macrophage infiltration in the renal cortex and medulla and renal proinflammatory cytokine (TNF-α and IL-1 β) levels were increased in I/R rats and further intensified in I/R+CAP rats (P<0.05), which were abolished by LC in both I/R and I/R+CAP groups. Mean arterial pressure (MAP) was elevated in I/R rats and further increased in I/R+CAP rats (P<0.05), which was prevented by LC in both I/R and I/R+CAP groups. Decreased creatinine clearance (Sham: 0.54±0.06, I/R: 0.28±0.02, I/R+CAP: 0.16±0.02, Sham+LC: 0.54±0.03, I/R+LC: 0.51±0.04, I/R+CAP+LC: 0.49±0.04 ml/min/100 gbwt, p<0.05) and increased levels of plasma urea, urinary 8-isoprostane, renal connective tissue growth factor (CTGF), and renal collage I and IV were observed in I/R rats and exacerbated in I/R+CAP rats (P<0.05), which were restored to normal levels by LC in both I/R and I/R+CAP groups. Thus, degeneration of TRPV1-positive nerves aggravates hypertension and renal inflammation and fibrosis induced by I/R and high salt intake, possibly via enhancing renal macrophage infiltration and function. These data suggest that activation of TRPV1 after renal injury conveys renal protection against inflammation and fibrosis via inhibiting macrophage infiltration.