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

有人认为HGF可能是急性肾损伤后组织重建的关键生理调节剂，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基因靶向技术，提供证据表明内源性HGF/c-Met轴在小鼠急性肾损伤后诱导肾再生中起重要作用，结果如下：(1)小鼠肾缺血再灌注后48小时肾小管增殖明显。当抗hgf IgG注入小鼠体内时，小管再生受到抑制，与骨髓植入增强有关。这些发现表明内源性HGF在肾缺血下诱导小管细胞增殖的重要性，而不是干细胞的参与。(2)已知70%部分肝切除术可减轻大鼠肌肉损伤后急性肾功能衰竭的发生。抗HGF IgG降低了70%肝切除术后肾损伤的保护作用，从而提示内源性HGF在挤压综合征后肝叶损失诱导下对肾损伤的保护作用。(3)采用Cre-LoxP系统制备足细胞特异性HGF基因缺失。在发育阶段，hgf缺陷小鼠的肾组织无明显病变。然而，缺乏hgf的小鼠似乎对一种化学药物更敏感，这种药物会导致蛋白尿。

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.