Bodin Sophie, Chollet Catherine, Goncalves-Mendes Nicolas, Gardes Joelle, Pean Franck, Heudes Didier, Bruneval Patrick, Marre Michel, Alhenc-Gelas François, Bouby Nadine
INSERM UMR 872, Centre de Recherche des Cordeliers, Paris, France.
Kidney Int. 2009 Aug;76(4):395-403. doi: 10.1038/ki.2009.208. Epub 2009 Jun 10.
Tissue kallikrein is the main kinin-forming enzyme in mammals, and differences in kinin levels are thought to be a contributing factor to diabetic nephropathy. Here, we determined the role of the kallikrein-kinin system in the pathogenesis of streptozotocin-induced diabetic nephropathy in wild-type and tissue kallikrein-knockout mice. All diabetic mice developed similar hyperglycemia, but the knockout mice had a significant two-fold increase in albuminuria compared to the wild-type mice before and after blood pressure elevation. Ezrin mRNA, a podocyte protein potentially implicated in albuminuria, was downregulated in the kidney of knockout mice. One month after induction of diabetes, the mRNAs of kininogen, tissue kallikrein, kinin B1, and B2 receptors were all increased up to two-fold in the kidney in both genotypes. Diabetes caused a 50% decrease in renal angiotensin-converting enzyme expression and a 20-fold increase in kidney injury molecule-1 reflecting tubular dysfunction, but there was no genotype difference. Our study found an early activation of the kallikrein-kinin system in the kidney and that this has a protective role against the development of diabetic nephropathy. The effect of tissue kallikrein deficiency on microalbuminuria in diabetic mice is similar to the effect of genetically high angiotensin-converting enzyme levels, suggesting that both observations, in part, result from a deficiency in kinins.
组织激肽释放酶是哺乳动物中主要的激肽生成酶，激肽水平的差异被认为是导致糖尿病肾病的一个因素。在此，我们确定了激肽释放酶 - 激肽系统在野生型和组织激肽释放酶基因敲除小鼠中链脲佐菌素诱导的糖尿病肾病发病机制中的作用。所有糖尿病小鼠均出现相似程度的高血糖，但与野生型小鼠相比，基因敲除小鼠在血压升高前后蛋白尿显著增加两倍。埃兹蛋白mRNA，一种可能与蛋白尿有关的足细胞蛋白，在基因敲除小鼠的肾脏中表达下调。糖尿病诱导一个月后，两种基因型小鼠肾脏中的激肽原、组织激肽释放酶、激肽B1和B2受体的mRNA均增加了两倍。糖尿病导致肾血管紧张素转换酶表达降低50%，反映肾小管功能障碍的肾损伤分子 - 1增加20倍，但不存在基因型差异。我们的研究发现肾脏中激肽释放酶 - 激肽系统早期激活，且这对糖尿病肾病的发展具有保护作用。组织激肽释放酶缺乏对糖尿病小鼠微量蛋白尿的影响与遗传上血管紧张素转换酶水平高的影响相似，这表明这两种观察结果部分是由于激肽缺乏所致。
