Rodríguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson R J
Renal Service and Department of Immunobiology (INBIOMED), Hospital Universitario, Maracaibo, Venezuela.
Kidney Int. 2001 Jun;59(6):2222-32. doi: 10.1046/j.1523-1755.2001.00737.x.
Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion.
Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks.
MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified.
SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.
间质单核细胞浸润是盐敏感性高血压（SSHTN）实验模型的一个特征。由于这些细胞的几种产物能够改变局部血管反应性和钠重吸收，我们研究了霉酚酸酯（MMF），一种已知可抑制免疫细胞浸润和增殖的药物，是否会改变由血管紧张素II（Ang II）输注诱导的SSHTN。
使用皮下微型泵给Sprague-Dawley大鼠输注Ang II两周。在第三周开始给予高钠（4% NaCl）饮食，并维持至第八周。在最初三周内，每天通过胃管给予MMF（30 mg/kg，N = 15），一种免疫抑制药物，或赋形剂（N = 15）。假手术大鼠（N = 9）用作对照。每周测定体重、血压（尾袖体积描记法）和血清肌酐。在Ang II输注结束时和八周时分析尿丙二醛（MDA）排泄、肾脏组织学和免疫组织学，包括Ang II和产超氧化物细胞的存在情况。
MMF治疗并未改变外源性Ang II输注期间诱导的高血压，但预防了随后的SSHTN。MMF治疗显著减轻了Ang II输注导致的肾小管间质损伤，增殖活性、T细胞浸润和活化（白细胞介素-2受体表达）、产超氧化物细胞以及尿MDA排泄也显著减轻。产生Ang II的细胞存在于SSHTN大鼠的肾小管间质中（8周时为60±30个Ang II阳性细胞/mm²），在MMF治疗组中减少了三分之二。浸润肾小管间质的淋巴细胞中有40% Ang II染色呈阳性。肾脏中Ang II受体的表达未改变。
Ang II输注导致的SSHTN与产生Ang II的免疫细胞浸润和活化有关。MMF治疗可减轻这些特征并预防SSHTN的发生。
