Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation.
Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation.
复制标题
DOI：
10.1042/cs20130223
复制
发表时间：
2014-05
期刊：
影响因子：
6
通讯作者：
Guangyu Zhou;A. Cheung;Xia Liu;Yufeng Huang
中科院分区：
文献类型：
--
作者：
Guangyu Zhou;A. Cheung;Xia Liu;Yufeng Huang
较高剂量的 AngII（血管紧张素 II）阻滞剂旨在优化白蛋白尿的减少，而不是控制慢性肾病患者的血压。然而，高剂量 AngII 阻滞剂的长期肾脏保护作用尚未明确。本研究旨在确定最大程度地减少蛋白尿的 ARB（AngII 受体阻滞剂）剂量是否可以减缓未切除肾的 db/db 小鼠（2 型糖尿病模型）中肾小球硬化的进展。未经治疗的未肾切除的 db/db 小鼠血压正常，但在 18 至 22 周龄期间出现进行性白蛋白尿和系膜基质扩张，这与 TGFβ1（转化生长因子 β1）、PAI-1（纤溶酶原激活剂抑制剂-1）、IV 型胶原和 FN（纤连蛋白）的肾表达增加有关。在 18 至 22 周龄的 db/db 小鼠的饮用水中使用缬沙坦进行治疗（之前确定的剂量可最大程度地减少蛋白尿），可防止未治疗的 db/db 小鼠中出现的蛋白尿和肾纤维化标志物的增加。此外，在未经治疗的糖尿病小鼠肾小球中，WT-1（Wilms 肿瘤蛋白-1）免疫阳性足细胞数量较低。在 18 至 22 周龄的糖尿病小鼠中，podocin 和 nephrin 的表达持续下降。这些变化表明足细胞损伤，服用缬沙坦可以显着改善这些变化。在糖尿病小鼠的疾病进展过程中，TNFα（肿瘤坏死因子α）、MCP-1（单核细胞趋化蛋白-1）、Nox2（NADPH氧化酶2）、p22phox和p47phox的肾脏表达以及尿液TBARS（硫代巴比妥酸反应物质）水平（肾脏炎症和氧化应激的标志物）增加。缬沙坦治疗被证明可以减少这些标志物。因此，高剂量的缬沙坦不仅最大限度地减少蛋白尿，而且还可以通过减少足细胞损伤以及肾脏氧化应激和炎症来阻止2型糖尿病引起的肾小球硬化的进展。
Higher doses of AngII (angiotensin II) blockers are intended to optimize albuminuria reduction rather than for blood pressure control in chronic kidney disease. However, the long-term renoprotection of high-dose AngII blockers has yet to be defined. The present study sought to determine whether doses of ARB (AngII receptor blocker) that maximally reduce proteinuria could slow the progression of glomerulosclerosis in the uninephrectomized db/db mouse, a model of Type 2 diabetes. Untreated uninephrectomized db/db mice had normal blood pressure, but developed progressive albuminuria and mesangial matrix expansion between 18 and 22 weeks of age, which was associated with increased renal expression of TGFβ1 (transforming growth factor β1), PAI-1 (plasminogen-activator inhibitor-1), type IV collagen and FN (fibronectin). Treatment with valsartan in the drinking water of db/db mice from 18 to 22 weeks of age, at a dose that was determined previously to maximally reduce proteinuria, prevented the increases in albuminuria and the markers of renal fibrosis seen in untreated db/db mice. In addition, WT-1 (Wilms tumour protein-1)-immunopositive podocyte numbers were found to be lower in the untreated glomeruli of mice with diabetes. The expression of podocin and nephrin were continually decreased in mice with diabetes between 18 and 22 weeks of age. These changes are indicative of podocyte injury and the administration of valsartan ameliorated them substantially. Renal expression of TNFα (tumour necrosis factor α), MCP-1 (monocyte chemoattractant protein-1), Nox2 (NADPH oxidase 2), p22phox and p47phox and urine TBARS (thiobarbituric acid-reacting substance) levels, the markers of renal inflammation and oxidative stress, were increased during disease progression in mice with diabetes. Valsartan treatment was shown to reduce these markers. Thus high doses of valsartan not only reduce albuminuria maximally, but also halt the progression of the glomerulosclerosis resulting from Type 2 diabetes via a reduction in podocyte injury and renal oxidative stress and inflammation.