Tschöpe C, Reinecke A, Seidl U, Yu M, Gavriluk V, Riester U, Gohlke P, Graf K, Bader M, Hilgenfeldt U, Pesquero J B, Ritz E, Unger T
Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, D-12200 Berlin.
Am J Physiol. 1999 Dec;277(6):H2333-40. doi: 10.1152/ajpheart.1999.277.6.H2333.
A reduction of renal kallikrein has been found in non-insulin-treated diabetic individuals, suggesting that an impaired renal kallikrein-kinin system (KKS) contributes to the development of diabetic nephropathy. We analyzed relevant components of the renal KKS in non-insulin-treated streptozotocin (STZ)-induced diabetic rats. Twelve weeks after a single injection of STZ, rats were normotensive and displayed hyperglycemia, polyuria, proteinuria, and reduced glomerular filtration rate. Blood bradykinin (BK) levels and prekallikrein activity were significantly increased compared with controls. Renal kallikrein activity was reduced by 70%, whereas urinary BK levels were increased up to threefold. Renal kininases were decreased as indicated by a 3-fold reduction in renal angiotensin-converting enzyme activity and a 1.8-fold reduction in renal expression of neutral endopeptidase 24.11. Renal cortical expression of kininogen and B2 receptors was enhanced to 1.4 and 1. 8-fold, respectively. Our data suggest that increased urinary BK levels found in severely hyperglycemic STZ-diabetic rats are related to increased filtration of components of the plasma KKS and/or renal kininogen synthesis in combination with decreased renal kinin-degrading activity. Thus, despite reduced renal kallikrein synthesis, renal KKS is activated in the advanced stage of diabetic nephropathy.
在未接受胰岛素治疗的糖尿病患者中发现肾激肽释放酶减少，这表明肾激肽释放酶 - 激肽系统（KKS）受损促成了糖尿病肾病的发展。我们分析了未接受胰岛素治疗的链脲佐菌素（STZ）诱导的糖尿病大鼠肾KKS的相关成分。单次注射STZ后12周，大鼠血压正常，但出现高血糖、多尿、蛋白尿和肾小球滤过率降低。与对照组相比，血缓激肽（BK）水平和前激肽释放酶活性显著增加。肾激肽释放酶活性降低了70%，而尿BK水平增加了两倍。肾激肽酶减少，表现为肾血管紧张素转换酶活性降低3倍，中性内肽酶24.11的肾表达降低1.8倍。肾皮质激肽原和B2受体的表达分别增强至1.4倍和1.8倍。我们的数据表明，在严重高血糖的STZ糖尿病大鼠中发现的尿BK水平升高与血浆KKS成分的滤过增加和/或肾激肽原合成增加以及肾激肽降解活性降低有关。因此，尽管肾激肽释放酶合成减少，但在糖尿病肾病晚期肾KKS仍被激活。
