Quiroz Y, Pons H, Gordon K L, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson R J, Rodríguez-Iturbe B
Renal Service and Department of Immunobiology (INBIOMED), Hospital Universitario de la Universidad del Zulia, Maracaibo 4001-A, Venezuela.
Am J Physiol Renal Physiol. 2001 Jul;281(1):F38-47. doi: 10.1152/ajprenal.2001.281.1.F38.
Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.
近期研究表明，肾脏中细微的微血管和肾小管间质损伤可导致盐敏感性高血压。为验证这一假说，我们确定了短暂阻断一氧化氮（NO）合成所诱导的轻度肾脏疾病是否会导致盐敏感性高血压，以及联合给予免疫抑制剂霉酚酸酯（MMF）预防肾脏损伤是否会阻止盐敏感性的发展。将N（ω）-硝基-L-精氨酸甲酯（L-NAME；饮用水中浓度为70 mg/100 ml）给予有或无MMF（经胃灌胃，30 mg·kg⁻¹·d⁻¹）的大鼠3周，随后为1周的“洗脱期”，此期间继续给予MMF，接着将动物置于高盐（4% NaCl）饮食中再喂养4周。在第3周和第8周检查肾脏组织学，并连续测量血压。L-NAME治疗导致急性高血压和轻度肾脏损伤。在洗脱期，血压恢复正常，但动物暴露于高盐饮食时血压又回到高血压范围。MMF治疗可预防因高盐饮食引起的高血压发展。这与MMF抑制肾脏损伤特定方面的能力相关，包括节段性肾小球硬化的发展、T细胞和血管紧张素II阳性细胞的浸润以及入球小动脉增厚。
