Kudo Yoshihiro, Kakinuma Yoshihiko, Iguchi Mitsuko, Sato Takayuki, Sugiura Tetsuro, Furihata Mutsuo, Shuin Taro
Department of Clinical Laboratory Medicine, Kochi Medical School, Kochi, Japan.
Nephron Exp Nephrol. 2007;106(3):e97-106. doi: 10.1159/000103022. Epub 2007 May 22.
BACKGROUND/AIMS: We previously demonstrated that angiotensin II (AII) combined with Habu snake venom (HV) induces glomerulonephritis (GN) in rats, with lesions being restricted to the glomeruli 2 days after the administration of both reagents, but the mechanisms inducing GN are unclear. We also indicated a role for hypoxia-inducible factor (HIF)-1alpha in attenuating the progression of GN. However, a role of the von Hippel-Lindau (VHL) protein in GN and mechanisms by which HV regulates the pathogenesis of GN remains unclear.
Immunohistochemical analysis revealed that VHL is weakly expressed in the renal tubules alone; however, HV caused elevated VHL expression in the injured glomeruli including endothelial cells and partially podocytes. Western blot analysis revealed that VHL expression was increased in HV-treated kidney compared with AII-treated or normal kidney. An in vitro study also showed HV-induced elevation in VHL expression. To investigate whether VHL pre-induction causes GN aggravation, we utilized thrombin, an inducer of VHL. Thrombin alone did not cause renal injuries; however, thrombin pre-treatment accelerated the development of GN even 1 day after treatment.
We suggest that VHL pre-induction by thrombin aggravates GN, and that the increase in VHL expression due to HV might be involved in accelerating onset of GN.
背景/目的：我们之前证明，血管紧张素II（AII）联合蝮蛇毒（HV）可诱导大鼠肾小球肾炎（GN），在两种试剂给药后2天，病变局限于肾小球，但诱导GN的机制尚不清楚。我们还指出缺氧诱导因子（HIF）-1α在减轻GN进展中起作用。然而，冯·希佩尔-林道（VHL）蛋白在GN中的作用以及HV调节GN发病机制仍不清楚。
免疫组织化学分析显示，VHL仅在肾小管中弱表达；然而，HV导致包括内皮细胞和部分足细胞在内的受损肾小球中VHL表达升高。蛋白质印迹分析显示，与AII处理的肾脏或正常肾脏相比，HV处理的肾脏中VHL表达增加。体外研究也显示HV诱导VHL表达升高。为了研究VHL预诱导是否会加重GN，我们使用了VHL诱导剂凝血酶。单独使用凝血酶不会导致肾损伤；然而，凝血酶预处理即使在治疗后1天也加速了GN的发展。
我们认为凝血酶预诱导VHL会加重GN，并且HV导致的VHL表达增加可能参与加速GN的发病。
