Pfeilschifter J, Bauer C
Physiologisches Institut, Universität Zürich, Switzerland.
Biochem J. 1987 Nov 15;248(1):209-15. doi: 10.1042/bj2480209.
Pretreatment with pertussis toxin inhibits angiotensin II-induced activation of polyphosphoinositide phosphodiesterase in rat renal mesangial cells [Pfeilschifter & Bauer (1986) Biochem. J. 236, 289-294]. Furthermore, activation of protein kinase C by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and by 1-oleoyl-2-acetylglycerol (OAG) abolishes angiotensin II-induced formation of inositol trisphosphate (IP3) in mesangial cells [Pfeilschifter (1986) FEBS Lett. 203, 262-266]. Using membrane preparations of [3H]inositol-labelled mesangial cells we tried to obtain further insight as to the step at which protein kinase C might interfere with the signal transduction mechanism in mesangial cells. Angiotensin II (100 nM) stimulates IP3 formation from membrane preparations of [3H]inositol-labelled mesangial cells with a half-maximal potency of 1.1 nM. The angiotensin II-induced formation of IP3 is enhanced by GTP. This effect of angiotensin II is completely blocked by the competitive antagonist [Sar1,Ala8]angiotensin II. Guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) and guanosine 5'-[beta gamma-imido]triphosphate (Gpp[NH]p), non-hydrolysable analogues of GTP, stimulate IP3 production in the absence of angiotensin II with Kd values of 0.19 microM and 2.4 microM, respectively. Angiotensin II augments the increase in IP3 formation induced by GTP gamma S. However, when mesangial cells were pretreated with TPA there was a dose-dependent inhibition of the synergistic action of angiotensin II on GTP gamma S-induced IP3 production. Comparable results are obtained with OAG, while the non-tumour-promoting phorbol ester 4 alpha-phorbol 12,13-didecanoate is without effect. These results suggest that activation of protein kinase C in mesangial cells does not impair phosphoinositide hydrolysis by stable GTP analogues but somehow seems to interfere with the stimulatory interaction of the occupied angiotensin II receptor with the transducing G-protein.
百日咳毒素预处理可抑制血管紧张素 II 诱导的大鼠肾系膜细胞中多磷酸肌醇磷酸二酯酶的激活[Pfeilschifter 和 Bauer（1986 年），《生物化学杂志》236 卷，289 - 294 页]。此外，佛波酯 12 - O - 十四酰佛波醇 13 - 乙酸酯（TPA）和 1 - 油酰 - 2 - 乙酰甘油（OAG）激活蛋白激酶 C 后，可消除血管紧张素 II 诱导的系膜细胞中肌醇三磷酸（IP3）的形成[Pfeilschifter（1986 年），《欧洲生物化学学会联合会快报》203 卷，262 - 266 页]。我们使用[3H]肌醇标记的系膜细胞的膜制剂，试图进一步了解蛋白激酶 C 可能干扰系膜细胞信号转导机制的步骤。血管紧张素 II（100 nM）刺激[3H]肌醇标记的系膜细胞膜制剂中 IP3 的形成，半数最大效应浓度为 1.1 nM。血管紧张素 II 诱导的 IP3 形成可被 GTP 增强。血管紧张素 II 的这种作用被竞争性拮抗剂[Sar1，Ala8]血管紧张素 II 完全阻断。鸟苷 5'-[γ - 硫代]三磷酸（GTPγS）和鸟苷 5'-[βγ - 亚氨基]三磷酸（Gpp[NH]p），GTP 的不可水解类似物，在无血管紧张素 II 时刺激 IP3 的产生，Kd 值分别为 0.19 μM 和 2.4 μM。血管紧张素 II 增强了 GTPγS 诱导的 IP3 形成的增加。然而，当系膜细胞用 TPA 预处理后，血管紧张素 II 对 GTPγS 诱导的 IP3 产生的协同作用出现剂量依赖性抑制。用 OAG 可得到类似结果，而无促肿瘤作用的佛波酯 4α - 佛波醇 12,13 - 二癸酸酯则无此作用。这些结果表明，系膜细胞中蛋白激酶 C 的激活并不损害稳定的 GTP 类似物诱导的磷酸肌醇水解，但似乎以某种方式干扰了被占据的血管紧张素 II 受体与转导 G 蛋白之间的刺激相互作用。
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