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GW24-e2192 NK-1 Receptor-mediated Renal Injury during DOCA-salt Hypertension
  1. Youping Wang1,
  2. Lin Cui1,
  3. Weihong Liu1,
  4. Mingjun Zhu1,
  5. Si Shen1,
  6. Donna H Wang2
  1. 1Central Laboratory and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China
  2. 2Department of Medicine, Michigan State University, East Lansing, MI 48824, USA


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).

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