Wu Y-G, Lin H, Qian H, Zhao M, Qi X-M, Wu G-Z, Lin S-T
Department of Nephropathy, the First Affiliated Hospital of AnHui Medical University, 230022, Hefei, China.
Inflamm Res. 2006 May;55(5):192-9. doi: 10.1007/s00011-006-0070-4.
Previously it was shown that blocking of the renin-angiotensin system (RAS) by angiotensin converting enzyme (ACE) inhibitors, or suppression of inflammatory responses by immunosuppressive drugs such as mycophenolate mofetil (MMF) could attenuate renal injury in diabetic rats. Whether RAS blockade combined with an immunosuppressive drug provides superior renoprotection against diabetic nephropathy has not been clearly delineated.
Diabetes was induced by injection of streptozotocin after uninephrectomy.
Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril (an ACE inhibitor, 10 mg/kg/d by gastric gavage), diabetes treated with MMF (10 mg/kg/d by gastric gavage), or diabetes treated with a combination of both agents and were followed for 8 weeks.
24 h urinary albumin excretion rate (AER) was determined, renal injury was evaluated, immunohistochemistry for ED-1 macrophage marker, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were performed, and expression of transforming growth factor (TGF)-beta1 protein was determined by Western blotting analysis.
Diabetes was associated with a considerable increase in AER. Both enalapril and MMF retarded the increase in albuminuria, which was nearly completely abrogated by combination therapy. Increased glomerular volume and tubulointerstitial injury index in diabetic rats was attenuated by treatment with either enalapril or MMF and further reduced by the combination of the two. Elevated malondialdehyde levels in renal tissue were reduced by enalapril or MMF and, more effectively, by combined enalapril with MMF. Renal overexpression of ICAM-1 was not retarded by enalapril and attenuated by MMF or combined enalapril with MMF. Combination therapy was associated with a superior suppression of diabetes-induced macrophage recruitment and overexpression of MCP-1 and TGFbeta1 compared to either monotherapy in renal tissue.
The combination of enalapril and MMF confers superiority over monotherapy in renoprotection, a mechanism which may be at least partly correlated with synergistic suppression of increased macrophage recruitment and overexpression of MCP-1 and TGF-beta1 in renal tissue in diabetic rats.
先前的研究表明，血管紧张素转换酶（ACE）抑制剂阻断肾素-血管紧张素系统（RAS），或霉酚酸酯（MMF）等免疫抑制药物抑制炎症反应，可减轻糖尿病大鼠的肾损伤。RAS阻断与免疫抑制药物联合使用是否能为糖尿病肾病提供更好的肾脏保护作用，目前尚未明确。
单侧肾切除术后注射链脲佐菌素诱导糖尿病。
将大鼠随机分为五组：对照组、糖尿病组、用依那普利（一种ACE抑制剂，通过胃管灌胃，剂量为10mg/kg/d）治疗的糖尿病组、用MMF（通过胃管灌胃，剂量为10mg/kg/d）治疗的糖尿病组、或用两种药物联合治疗的糖尿病组，并随访8周。
测定24小时尿白蛋白排泄率（AER），评估肾损伤，进行ED-1巨噬细胞标志物、细胞间黏附分子-1（ICAM-1）和单核细胞趋化蛋白-1（MCP-1）的免疫组化检测，并通过蛋白质印迹分析测定转化生长因子（TGF）-β1蛋白的表达。
糖尿病与AER显著增加相关。依那普利和MMF均延缓了蛋白尿的增加，联合治疗几乎完全消除了蛋白尿的增加。糖尿病大鼠肾小球体积增加和肾小管间质损伤指数通过依那普利或MMF治疗得到减轻，两者联合使用进一步降低。肾组织中丙二醛水平升高通过依那普利或MMF降低，依那普利与MMF联合使用更有效。依那普利未延缓ICAM-1在肾脏的过度表达，MMF或依那普利与MMF联合使用可减轻其过度表达。与单一疗法相比，联合治疗在抑制糖尿病诱导的巨噬细胞募集以及肾组织中MCP-1和TGFβ1的过度表达方面具有更好的效果。
依那普利和MMF联合使用在肾脏保护方面优于单一疗法，其机制可能至少部分与协同抑制糖尿病大鼠肾组织中巨噬细胞募集增加以及MCP-1和TGF-β1的过度表达有关。
