Molecular basis for renal regeneration : New approach using a nephron-specific HGF-knockout mice

有研究表明，肝细胞生长因子可能是急性肾损伤后组织重建的关键生理调节因子，但很少有直接证据支持这一假设。本研究利用抗HGF抗体或HGF基因打靶技术，证实了内源性HGF/c-Met轴在急性肾损伤后诱导小鼠肾脏再生中的重要作用，具体表现为：（1）肾缺血再灌注48小时，肾小管增生明显。当给予小鼠抗HGF IgG时，肾小管再生受到抑制，与骨髓植入的增强相关。这些发现表明，在肾缺血时，内源性HGF引起肾小管细胞增殖的重要性，而不是干细胞参与。(2)已知70%肝部分切除减轻了大鼠肌肉损伤后急性肾衰竭的发作。抗HGF IgG减弱了70%肝切除术对肾损伤的保护作用，因此表明由肝叶损失诱导的内源性HGF在挤压综合征后保护肾损伤中的关键作用。(3)我们利用Cre-LoxP系统制备了足细胞特异性的HGF基因缺失。在发育阶段，HGF缺陷小鼠的肾组织中没有明显的病变。然而，缺乏HGF的小鼠似乎对一种化学药物更敏感，这会导致蛋白尿。

It was suggested that HGF may be a key physiological regulator for tissue reconstruction after acute renal injuries, but there was little direct evidence for supporting this hypothesis. Herein we provide evidence to show that endohenous HGF/c-Met axis plays an important role for inducing renal regeneration in mice after acute renal injury, using anti-HGF antibody or HGF gene targeting techniques, as follows :(1) Renal tubular proliferation became evident in mice at 48-hr after renal ischemia and reperfusion. When anti-HGF IgG was administered into mice, tubular regeneration was inhibited, associated with the enhancement of bone marrow engraftment. These findings indicated the importace of endogenous HGF to elicit tubular cell proliferation, rather than stem cell involvement under renal ischemia.(2) Is is known that 70%-partial hepatectomy attenuated the onset of acute renal failure after muscular damages in rats. Anti-HGF IgG diminished the protection of renal injury by 70%-hepatectomy, hence indicating the pivotal roles of endogenous HGF, induced by the loss in hepatic lobes, for protection of renal damage after crush syndorome.(3) We prepared the podocyte-specific deletion of HGF gene, using a Cre-LoxP system. There was no significant lesions in the renal tissues of the HGF-deficient mice during a developmental stage. However, HGF-deficient mice seemed to be more sensitive to a chemical drug, which causes proteinuria.