Kakoki Masao, McGarrah Robert W, Kim Hyung-Suk, Smithies Oliver
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7576-81. doi: 10.1073/pnas.0701617104. Epub 2007 Apr 23.
To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1-/-/Bdkrb2-/-) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2-/-), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2'-deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-beta1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.
为了探究激肽释放酶 - 激肽系统在肾脏缺血/再灌注损伤中的作用，我们通过删除编码这两种受体的基因组区域，培育出了同时缺乏缓激肽B1和B2受体基因的小鼠（B1RB2R基因敲除小鼠，Bdkrb1-/-/Bdkrb2-/-）。在4月龄小鼠中，B1RB2R基因敲除小鼠、B2R基因敲除小鼠（Bdkrb2-/-）和野生型小鼠的血压无显著差异。双侧肾动脉闭塞30分钟并再灌注24小时后，死亡率、肾脏组织学和功能变化、总DNA中的8 - 羟基 - 2'-脱氧鸟苷水平、线粒体DNA缺失以及肾脏中TUNEL阳性细胞数量按以下顺序（从最低到最高）逐渐增加：野生型、B2R基因敲除小鼠、B1RB2R基因敲除小鼠。缺血/再灌注损伤后，转化生长因子 - β1、结缔组织生长因子和内皮素 - 1的mRNA水平升高也按相同顺序（从最低到最高）加剧：野生型、B2R基因敲除小鼠、B1RB2R基因敲除小鼠。因此，缓激肽B1和B2受体在减少肾脏缺血/再灌注损伤期间的DNA损伤、细胞凋亡、肾脏形态和功能变化以及死亡率方面均发挥重要作用。
