Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat
Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat
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DOI：
10.1681/asn.v113454
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发表时间：
2000-03-01
影响因子：
13.6
通讯作者：
Endre, ZH
中科院分区：
文献类型：
--
作者：
Gobé, G;Zhang, XJ;Endre, ZH
促进急性肾功能衰竭(ARF)细胞的存活和再生对肾功能的恢复具有重要意义。本研究分析了Bcl2基因家族促凋亡和抗凋亡成员(Bcl2，BclX，BAX，BAX，BAX，采用双侧肾动脉结扎30min，再灌注0~14d的大鼠缺血性ARF模型。对细胞凋亡和有丝分裂进行量化，并对其他细胞损伤进行定性评估，包括坏死和细胞黏附丧失。免疫组织化学方法检测Bcl2和生长因子蛋白的表达定位和表达水平。近端肾小管和远端肾小管的细胞凋亡在缺血后4~14d达到高峰。有丝分裂在近端肾小管2d达高峰，远端肾小管4~14d达高峰。缺血再灌注后抗凋亡基因家族成员与生长因子之间存在时空关系。对照组大鼠肾脏远端小管上皮细胞中Bcl2、BclX-L低表达。Bax在近端小管低至中度表达，远端小管低表达，EGF、IGF-1在远端小管低至中度表达，转化生长因子-β在近端小管低表达。而在再灌注24 h内，远端小管上皮细胞Bcl2表达明显增强，Bclx、L和Bax表达轻度增加。近曲小管Bax表达明显增加，BclX-L表达轻度增加。Bcl2蛋白表达增强后24 h，远端小管IGF-1和EGF蛋白表达水平升高，与Bcl2抗凋亡蛋白相似，在邻近近端小管中也可检测到IGF-1和EGF蛋白表达，提示这些小管具有旁分泌作用。在再生的近端小管中，转化生长因子-β的表达略有增加，但与Bcl-2基因的表达模式无关。对这些结果的解释是，远端小管通过抗凋亡基因促进存活而对缺血损伤具有适应性抵抗，其存活允许生长因子的表达，这些生长因子不仅对自身细胞群的维持和再生至关重要(自分泌作用)，而且对邻近缺血敏感的近端小管细胞(旁分泌作用)也至关重要。
The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-X-L, Bax) and epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and transforming growth factor-beta (TGF-beta), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 d in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-X-L was low in epithelium of distal tubules. Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-beta had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-X-L and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-X-L. Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-beta expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).