MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
J Am Soc Nephrol. 2012 Mar;23(3):405-11. doi: 10.1681/ASN.2011060577. Epub 2011 Dec 22.
Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.
啮齿动物模型仅表现出人类糖尿病肾病的最早特征，这限制了我们研究新疗法的能力。高血压是人类晚期糖尿病肾病的先决条件，因此典型啮齿动物模型中高血压的罕见性部分解释了它们对肾病的抵抗力。在这里，我们使用了 Cyp1a1mRen2 大鼠，其中鼠肾素-2 基因在细胞色素 P4501a1 启动子的控制下被整合。在这种转基因品系中，低剂量饮食吲哚-3-甲醇的给药会引起中度高血压。在没有高血压的情况下，链脲佐菌素诱导的糖尿病导致白蛋白尿增加 14 倍，但尽管有 28 周的明显高血糖，组织学和基因表达仍只有轻微变化。在诱导的高血压存在下，高血糖导致白蛋白尿增加 500 倍，明显的肾小球硬化和肾小管间质纤维化，并诱导了在人类糖尿病肾病肾小管间质中上调的许多相同途径。总之，尽管单独在啮齿动物中诱导糖尿病对模拟人类糖尿病肾病的作用有限，但肾素依赖性高血压和高血糖协同作用可再现人类中观察到的许多临床、组织学和基因表达变化。
