Bakris G L, Bhandaru S, Akerstrom V, Re R N
Department of Medicine, Alton Ochsner Medical Foundation New Orleans, Louisiana.
Am J Hypertens. 1994 Jul;7(7 Pt 1):583-90. doi: 10.1093/ajh/7.7.583.
Endothelin modulates human mesangial cell (HMC) proliferation in response to angiotensin II (Ang II). Angiotensin converting enzyme inhibitors (ACEIs) have variable effects on HMC growth depending on culture conditions. No studies, however, have investigated the effects of ACEIs on HMC production of endothelin-1 in either actively proliferating or quiescent HMCs. The present study was designed to evaluate the effects of ACEIs on HMC-associated mitogenesis, cell counts, and endothelin-1 production in the presence and absence of insulin in both quiescent and proliferating HMCs. It tests the hypothesis that ACEIs attenuate HMC growth through a reduction in HMC-associated endothelin-1 generation. The effects of four different ACEIs, an Ang II receptor antagonist, losartan, and a monoclonal antibody to endothelin-1 were evaluated. ACEIs inhibited HMC mitogenesis and cell counts in proliferative but not quiescent cells. This was due to the absence of ACE activity in HMCs and its presence in 10% fetal calf serum. Both ACEIs and losartan reduced endothelin-1 production per cell. Compared to vehicle, losartan reduced the amount of endothelin-1 in conditioned media to a greater extent than any ACEI (2.2 +/- 0.3, captopril v 1.9 +/- 0.5, quinaprilat v 3.8 +/- 0.3 delta pg/cell x 10(-3) endothelin-1, losartan; P < .05). Moreover, insulin potentiated the antimitogenic effects of both ACEIs and losartan on HMCs. Lastly, the attenuated increase of endothelin-1 in conditioned media and associated antimitogenic effect on HMCs with losartan alone was not potentiated by the addition of any ACEI to losartan. These data provide indirect evidence that Ang II production may occur in culture media when both its precursors and a sufficient amount of converting enzyme activity are present. This is predicated on the observation that HMCs lack ACE activity and that ACEIs blunt mitogenesis of proliferating HMCs. The kinetics of this reaction, as well as the mechanism of how insulin potentiates the antimitogenic effects of ACEIs, were not studied.
内皮素可调节人系膜细胞（HMC）对血管紧张素II（Ang II）的增殖反应。血管紧张素转换酶抑制剂（ACEIs）对HMC生长的影响因培养条件而异。然而，尚无研究探讨ACEIs对处于活跃增殖或静止状态的HMC产生内皮素-1的影响。本研究旨在评估ACEIs在有无胰岛素存在的情况下，对静止和增殖HMC中与HMC相关的有丝分裂、细胞计数及内皮素-1产生的影响。该研究检验了以下假设：ACEIs通过减少与HMC相关的内皮素-1生成来减弱HMC生长。评估了四种不同的ACEIs、一种Ang II受体拮抗剂氯沙坦以及一种抗内皮素-1单克隆抗体的作用。ACEIs抑制增殖细胞而非静止细胞中的HMC有丝分裂和细胞计数。这是由于HMC中不存在ACE活性，而其在10%胎牛血清中存在。ACEIs和氯沙坦均降低了每个细胞的内皮素-1产生量。与溶剂对照相比，氯沙坦比任何ACEI都能更大程度地降低条件培养基中内皮素-1的量（卡托普利为2.2±0.3，喹那普利拉为1.9±0.5，氯沙坦为3.8±0.3Δpg/细胞×10⁻³内皮素-1；P<0.05）。此外，胰岛素增强了ACEIs和氯沙坦对HMC的抗有丝分裂作用。最后，单独使用氯沙坦时，条件培养基中内皮素-1的增加减弱以及对HMC的相关抗有丝分裂作用，不会因向氯沙坦中添加任何ACEI而增强。这些数据间接证明，当同时存在血管紧张素II的前体和足够量的转换酶活性时，培养基中可能会发生血管紧张素II的产生。这基于以下观察结果：HMC缺乏ACE活性，且ACEIs可抑制增殖HMC的有丝分裂。本研究未探讨该反应动力学以及胰岛素增强ACEIs抗有丝分裂作用的机制。
