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GW23-e1148
ROLE OF CHEMOKINE RECEPTOR 2 IN RENAL INJURY DURING DOCA-SALT HYPERTENSION
  1. Cui Lin,
  2. Sun Miao,
  3. Liu Weihong,
  4. Gao Yuan,
  5. Shen Si,
  6. Zhu Mingjun,
  7. Wang Youping
  1. Central Laboratory, and Division of Cardiology, First Affiliated Hospital, Henan University of Traditional Chinese Medicine

    Abstract

    Objectives This study was designed to determine the role of chemokine receptor 2 (CCR2), a receptor of MCP-1, in the development of salt-sensitive hypertension-induced renal damage.

    Methods We induced hypertension by uninephrectomy and deoxycorticosterone (DOCA)-salt in C57BL/6 mice with or without a selective CCR2 antagonist, RS504393. Sham mice underwent uninephrectomy without receiving DOCA and saline.

    Results After 4 week treatment, systolic blood pressure (SBP) measured by tail-cuff method increased in the DOCA-salt-treated mice compared with the sham mice (142±7 vs 107±6 mm Hg, p<0.01). DOCA-salt treatment also induced renal hypertrophy, increased urinary albumin and 8-isoprostane excretion and decreased creatinine clearance compared with the sham mice (110.9±3.0 vs 75.6±1.9 mg/10 g body weight; 25.6±2.8 vs 5.7±0.4 µg/24 h; 1.63±0.22 vs 0.51±0.05 ng/24 h; 211±13 vs 336±17 ml/24 h, p<0.05). Periodic acid-Schiff staining showed that DOCA-salt treatment caused obvious glomerulosclrosis compared with the sham mice (0.41±0.05 vs 0.10±0.03, p<0.05). Masson trichrome staining revealed that tubulointerstitial injury in kidney also increased in the DOCA-salt-treated mice compared with the sham mice (2.29±0.36 vs 0.43±0.20, p<0.05). Immunostaining studies showed that DOCA-salt treatment increased monocyte/macrophage infiltration in kidney compared with the sham mice (43±4 vs 13±2 cells/mm2, p<0.05). Blockade of the CCR2 with RS504393 (4 mg/kg/day, sc) had no effect on SBP. However, they prevented renal morphological damage and inhibited the increase in urinary albumin and 8-isoprostane excretion and the decrease in creatinine clearance (p<0.05).

    Conclusions Our data showed that blockade of CCR2 with RS504393 prevented renal damage induced by DOCA-salt hypertension independently of their effects on blood pressure. The results suggest that CCR2-mediated monocyte/macrophage infiltration may contribute to renal damage induced by salt-sensitive hypertension.

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