Yamaguchi T, Fukase M, Sugimoto T, Chihara K
Department of Medicine, Kobe University School of Medicine, Japan.
Horm Metab Res. 1995 Mar;27(3):131-6. doi: 10.1055/s-2007-979924.
Although parathyroid hormone-related protein (PTHrP) is known to be secreted into the circulation as heterogeneous forms, with its N-terminal and C-terminal fragments as well as the intact form, the fate of these molecules in the plasma has not been fully understood. As for a C-terminal fragment, the kidney seems to be physiologically important in its metabolism, because it is elevated in circulating plasma in patients with chronic renal failure. In this study, we examined the mechanism by which a C-terminal fragment of PTHrP was metabolized by rat kidney and by other rat organs in vitro. When human (h) PTHrP-(109-141) was incubated for 2 h with an extract of rat kidney, it was almost completely hydrolyzed. This hydrolysis was readily blocked by the additions of o-phenanthrolline and dithiothreitol, indicating the participation in this process of a metallo-protease possessing disulfide bonds. This hydrolytic activity showed a meprin-like character, with being sensitive to actinonin but not to phosphoramidon. Furthermore, the participation of meprin itself in this process was directly confirmed by the experiment comparing degradation products of the peptide by the microvillar membranes of rat kidney with those by a purified rat meprin, in which a large part of the metabolites by rat kidney membranes corresponded to those by rat meprin. Among other rat organs examined, the extracts of the small intestine pancreas, spleen and urinary bladder exerted remarkable hydrolytic activities for hPTHrP-(109-141).(ABSTRACT TRUNCATED AT 250 WORDS)
尽管已知甲状旁腺激素相关蛋白（PTHrP）以多种形式分泌到循环中，包括其N端和C端片段以及完整形式，但这些分子在血浆中的命运尚未完全清楚。至于C端片段，肾脏在其代谢中似乎具有重要的生理意义，因为在慢性肾衰竭患者的循环血浆中其水平会升高。在本研究中，我们研究了PTHrP的C端片段在体外被大鼠肾脏和其他大鼠器官代谢的机制。当人（h）PTHrP-（109-141）与大鼠肾脏提取物孵育2小时时，它几乎被完全水解。这种水解很容易被邻菲罗啉和二硫苏糖醇阻断，表明参与此过程的是一种具有二硫键的金属蛋白酶。这种水解活性表现出类meprin的特征，对放线菌素敏感但对磷酰胺素不敏感。此外，通过比较大鼠肾脏微绒毛膜和纯化的大鼠meprin对该肽的降解产物的实验，直接证实了meprin本身参与了这一过程，其中大鼠肾脏膜产生的大部分代谢产物与大鼠meprin产生的代谢产物相对应。在检测的其他大鼠器官中，小肠、胰腺、脾脏和膀胱的提取物对hPTHrP-（109-141）具有显著的水解活性。（摘要截短于250字）
