PDF(Pubmed)
Abstract：
Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.
摘要：
Renin,天冬氨酸蛋白酶,通过将其唯一已知的底物血管紧张素原裂解为血管紧张素来调节肾素-血管紧张素系统。最近的研究表明，肾素也可能切割补体成分C3以激活补体或导致其失调。通常,C3被C3转化酶切割，使用丝氨酸残基的羟基作为亲核试剂的丝氨酸蛋白酶。这里,我们提供了7行证据表明肾素不会切割C3。首先,C3肾小球病变（C3G）和非典型溶血性尿毒症综合征（aHUS）患者的肾素血浆水平和C3水平之间没有关联，这意味着在高肾素存在下，血清C3消耗不会增加。第二,当来自高肾素水平患者的血清与来自正常/低肾素水平患者的血清进行比较时,C3转化为C3b的体外试验未检测到差异。第三，Aliskiren,肾素抑制剂,不会阻断液相中肾病因子引入的异常补体活性。第四，阿利吉仑不会阻断细胞表面的补体活性失调。第五,来自不同来源的重组肾素即使在37℃孵育24小时后也不会切割C3。第六,将重组肾素直接掺入C3G和aHUS患者的血清样品中不会增强液相或细胞表面的补体活性。第七，分子建模和对接将C3放置在肾素活性位点的位置，该位置与催化水解的生产性基态复合物不一致。因此，我们的研究不支持肾素在补体激活中的作用.
