Objectives Salt-sensitive hypertension is a leading risk factor contributing to the development of chronic renal disease. We found that high-salt intake activated sensory nerves, leading to release of sensory neuropeptides including substance P (SP). It is well established that the neurokinin-1 receptor (NK-1R) is activated preferentially by SP. This study was designed to determine whether activation of NK-1R contributes to the development of renal injury during DOCA-salt hypertension.
Methods We induced salt-sensitive hypertension by uninephrectomy and deoxycorticosterone (DOCA)-salt in C57BL/6 mice with or without selective NK1 antagonists.
Results DOCA-salt treatment for 5 weeks increased mean arterial pressure (MAP) determined by the telemetry system (144 ± 3 vs. 108 ± 4 mmHg, P < 0.01) and renal hypertrophy (116.3 ± 2.7 vs. 75.7 ± 1.4 mg/10 g of BW, P < 0.01) compared with sham mice. We also found that urinary 8-isoprostane and albumin excretion were increased in DOCA-salt mice compared with sham mice (1.76 ± 0.16 vs. 0.49 ± 0.10 ng/24 h; 41.1 ± 3.5 vs. 5.8 ± 0.6 μg/24 h, P < 0.05). Periodic acid-Schiff and Masson’s trichrome staining showed that DOCA-salt treatment caused obvious glomerulosclerosis and tubulointerstitial injury in the renal cortex (0.62 ± 0.06 vs. 0.08 ± 0.01; 3.00 ± 0.30 vs. 0.21 ± 0.10, P < 0.05), and tubulointerstitial fibrosis compared with the sham mice. Consistent with the results, renal collagen level determined using hydroxyproline assay was higher in DOCA-salt treated mice compared with the sham mice (26.8 ± 2.4 vs. 12.2 ± 1.3 μg/mg dry tissue, P < 0.05). In addition, F4/80-staining showed that interstitial monocyte/macrophage infiltration were greater in DOCA-salt mice compared with sham mice (61 ± 4 vs. 9 ± 2 cells/mm2, P < 0.05). Blockade of the NK-1R with RP-67580 (8 mg/kg/day, ip) or L-733,060 (20 mg/kg/day, ip) had no effect on MAP and renal hypertrophy. However, the NK-1R antagonists attenuated renal morphological injury, interstitial monocyte/macrophage infiltration, and the increase in renal collagen, and reduced the increase in urinary 8-isoprostane and albumin excretion in DOCA-salt treated mice (P < 0.05).
Conclusions Our study showed that blockade of NK-1R with RP-67580 or L-733,060 attenuated renal injury induced by DOCA-salt hypertension independently of their effects on blood pressure. The results suggest that activation of NK-1R, possibly by SP, may contribute to renal injury during DOCA-salt hypertension. This work was supported by the National Natural Science Foundation of China (No. 81170243).