A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)
A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)
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DOI：
10.1046/j.1523-1755.1998.00019.x
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发表时间：
1998-08-01
影响因子：
19.6
通讯作者：
Skinner, SL
中科院分区：
文献类型：
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作者：
Kelly, DJ;Wilkinson-Berka, JL;Skinner, SL
背景组织中的肾素-血管紧张素系统（RAS）可调节糖尿病肾脏的结构和功能变化。在6周龄时给予表现出组织肾素表达增加的高血压转基因（mREN-2）27大鼠（TGR）链脲佐菌素（STZ，糖尿病）或柠檬酸盐缓冲液（非糖尿病），并在4周和12周后处死。其他组在STZ或载体后用血管紧张素转化酶抑制剂培哚普利治疗12周。以18周龄非糖尿病和糖尿病自发性高血压大鼠（SHR）为对照。在糖尿病TGR中，STZ 12周后观察到最鲜艳的病变，肾脏表现为空泡化小管、透明质化小动脉、髓样纤维化和坏死以及严重的肾小球硬化。与此相反，只有轻度肾小球硬化被认为是在非糖尿病TGR和糖尿病SHR。糖尿病4周后TGR和糖尿病12周后SHR的肾小球滤过率增加，但TGR糖尿病12周后下降超过50%。在TGR和SHR中，糖尿病增加蛋白尿，但不改变收缩压。在糖尿病TGR中，肾脏肾素含量进行性增加，这与肾小球体（JGA）中的肾素免疫标记增加和近曲小管中的肾素出现有关。与此相反，肾脏肾素含量和JGA肾素免疫标记在糖尿病SHR不变。培哚普利可减轻糖尿病TGR患者肾脏病理改变，改善肾功能，消除近端肾小管肾素免疫标记。这是第一次报告的糖尿病啮齿动物模型发展迅速发病的肾损害。此外，这项研究表明激活的肾脏RAS在加速糖尿病肾病中的作用，并证实了抑制该系统的药物的益处。
Background. The tissue renin-angiotensin system (RAS) may modulate the structural and functional changes that occur in the diabetic kidney.Methods. Hypertensive transgenic (mREN-2)27 rat (TGR) that exhibit increased tissue renin expression were administered streptozotocin (STZ, diabetic) or citrate buffer (non-diabetic) at six weeks of age, and sacrificed 4 and 12 weeks later. Further groups were treated for 12 weeks post-STZ or vehicle with the angiotensin converting enzyme inhibitor, perindopril. Comparisons were made with 18-week-old non-diabetic and diabetic spontaneously hypertensive rats (SHR).Results. In diabetic TGR, the most florid lesion was seen after 12 weeks of STZ, with kidneys exhibiting vacuolated tubules, hylanized arterioles, medullary fibrosis and necrosis and severe glomerulosclerosis. In contrast, only mild glomerulosclerosis was seen in non-diabetic TGR and diabetic SHR. Glomerular filtration rate was increased after four weeks of diabetes in TGR and 12 weeks of diabetes in SHR, but declined by greater than 50% after 12 weeks of diabetes in TGR. In both TGR and SHR, diabetes increased albuminuria but did not modify systolic blood pressure. Renal renin content increased progressively in diabetic TGR, and this was associated with increased renin immunolabeling in the juxtaglomerular apparatus (JGA) and the appearance of renin in proximal convoluted tubules. In contrast, renal renin content and JGA renin immunolabeling were unchanged in diabetic SHR. Perindopril attenuated renal pathology, improved renal function and abolished proximal tubular renin immunolabeling in diabetic TGR.Conclusions. This is the first report of a diabetic rodent model developing rapid onset renal impairment. Furthermore, this study suggests a role for an activated renal RAS in the acceleration of diabetic renal disease and confirms the benefit of drugs that inhibit this system.