INDUCTION OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR MRMA IN RAT-KIDNEY AFTER ACUTE INJURY
INDUCTION OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR MRMA IN RAT-KIDNEY AFTER ACUTE INJURY
复制标题
DOI：
10.1172/jci118087
复制
发表时间：
1995-08-01
影响因子：
15.9
通讯作者：
HARRIS, RC
中科院分区：
文献类型：
--
作者：
HOMMA, T;SAKAI, M;HARRIS, RC
先前的研究表明，EGF 或 EGF 促有丝分裂蛋白家族的其他成员参与肾脏损伤恢复过程中发生的肾小管上皮细胞的增殖。本研究检查了最近发现的肝素结合 EGF 样生长因子 (HB-EGF) 的 mRNA 表达是否受到缺血/再灌注或氯化汞诱导的肾损伤的调节。大鼠单侧缺血/再灌注 45 分钟内，缺血后肾脏中 HB-EGF mRNA 的表达增加，仅当缺血再灌注时才发生 HB-EGF mRNA 的诱导，并且不会通过通过盐水灌注从缺血后肾脏去除血细胞而消除。与 HB-EGF 的 S-35 标记反义核糖核酸探针原位杂交表明，与与对照相比，缺血后6 h肾脏内皮质和外髓质的HB-EGF mRNA表达增加，呈斑片状分布，其中外髓质内条纹表达量最大。表达主要发生在肾小管上皮细胞中，重组人HB-EGF在兔近曲小管细胞和NRK 52E正常大鼠肾上皮细胞的原代培养物中刺激[H-3]胸苷掺入，其效力与EGF相似。当肾小管在缺氧条件下孵育后进行复氧时，在从大鼠肾皮质或外髓质新鲜分离的肾小管中观察到HB-EGF mRNA的诱导，肾毒素氯化汞也在体内和离体大鼠皮质小管中引起 HB-EGF mRNA 的诱导，离体肾小管中缺氧/复氧诱导的 HB-EGF mRNA 表达被自由基清除剂二甲基硫脲和四甲基硫脲抑制，表明活性氧的参与。这些发现表明 HB-EGP mRNA 在体内肾脏中可通过急性肾小管损伤诱导，并提示HB-EGF 可能作为一种自分泌/旁分泌生长因子，参与肾小管上皮细胞的增殖和肾脏的修复。
Previous studies have suggested that EGF or other members of the EGF family of mitogenic proteins are involved in proliferation of renal tubular epithelial cells occurring during recovery from injury to the kidney, The present studies examined whether expression of mRNA for the recently identified heparin-binding EGF-like growth factor (HB-EGF) is regulated in response to renal injury induced by either ischemia/reperfusion or mercuric chloride. Increased expression of HB-EGF mRNA was demonstrated in the post-ischemic kidney within 45 min of unilateral ischemia/reperfusion in the rat, Induction of HB-EGF mRNA occurred only when ischemia was followed by reperfusion, and was not eliminated by removal of blood cells from the post-ischemic kidney by saline perfusion, In situ hybridization with S-35-labeled antisense riboprobes of HB-EGF indicated that compared with control, there was increased HB-EGF mRNA expression in the 6 h post-ischemic kidney in the inner cortex and outer medulla in a patchy distribution, with the greatest expression in the inner stripe of the outer medulla. Expression occurred primarily in tubular epithelial cells, Recombinant human HB-EGF stimulated [H-3]thymidine incorporation in both primary cultures of rabbit proximal tubule cells and NRK 52E normal rat kidney epithelial cells, with potency similar to that of EGF, Induction of HB-EGF mRNA was observed in tubules freshly isolated from rat renal cortex or outer medulla when the tubules were subjected to reoxygenation after incubation in anoxic conditions, The nephrotoxin, mercuric chloride, also caused induction of HB-EGF mRNA both in vivo and in isolated rat cortical tubules, The anoxia/reoxygenation-induced expression of HB-EGF mRNA in isolated tubules was inhibited by the free radical scavengers, di- and tetra-methylthiourea, indicating involvement of reactive oxygen species, These findings indicate that HB-EGP mRNA is inducible in the kidney in vivo by acute tubular injury and suggest that HB-EGF may act as an autocrine/paracrine growth factor involved in proliferation of tubular epithelial cells and repair of the kidney.