丝裂素活化蛋白激酶信号转导途径对血小板源生长因子所致鼠肾系膜细胞表型转化的调控作用  

Regulatory effects of signal transduction through MAPK pathways on PDGF-induced phenotypic change in rat glomerular mesangial cells

作　　者：李晓玫[1,2] 唐嘉薇[1,2] 李彪[1,2] 侯平[1,2] 

机构地区：[1]北京大学第一医院肾内科 [2]北京大学肾脏病研究所,100034

出　　处：《中华肾脏病杂志》2000年第6期347-351,共5页Chinese Journal of Nephrology

基　　金：国家自然科学基金资助项目!(39770346);教育部跨世纪人才基金资助项目!(39910210474-231-C04)

摘　　要：目的 研究血小板源生长因子（ＰＤＧＦ）对肾小球系膜细胞（ＭＣ）表型转化的影响，并探讨丝裂素活化蛋白激酶（ＭＡＰＫ）信号转导途径在其作用中的调控机制。方法 以体外培养的大鼠ＭＣ为对象，观察ＰＤＧＦ对细胞增殖、α－平滑肌肌动蛋白（ＳＭＡ）表达和细胞内ｃ－Ｊｕｎ氨基末端激酶（ＪＮＫ）活性的作用；观察细胞外信号调节激酶（ＥＲＫ）途径上游信号ＭＥＫ－１阻断剂ＰＤ９８０５９对ＰＤＧＦ所致上述作用的影响；应用ｒａｆ－１基因转染并稳定高表达的ＭＣ观察其对α－ＳＭＡ表达、细胞形态及其超微结构的影响。结果 ＰＤＧＦ可刺激ＭＣ持续增殖；刺激６～４８ ｈ可使α－ＳＭＡ表达增加，但持续刺激７２ ｈ以上则可导致其表达被抑制近５０％。ＰＤＧＦ对ＪＮＫ活性无明显影响，阻断ＥＲＫ活化不影响ＪＮＫ活性及ＰＤＧＦ对α－ＳＭＡ表达的短时刺激作用。Ｒａｆ－ｌ蛋白激酶稳定高表达的ＭＣ细胞内α－ＳＭＡ表达缺失，同时细胞内微丝、微管结构减少，细胞形态改变。结论ＰＤＧＦ对系膜细胞表型转化的影响表现为促进细胞持续增殖、短时作用刺激α－ＳＭＡ表达而持续作用则抑制α－ＳＭＡ表达，提示其为具有调控ＭＣ增殖和分化双重作用的细胞因子。Objective To investigate effects of PDGF on phenotypic change of glomerular mesangial cells(MC), and study intracellular mechanisms through mitogen-activated- protein kinase (MAPK) pathways. Methods After stimulation with PDGF, cell proliferation and expression of α-smooth muscle actin(α-SMA) were detected in cultured rat MC. Expression of α-SMA and activity of JNK, which may be a intracellular signaling event in cell differentiation, was measured with or without antagonist of MEK-1. Then MC was stably transfected with constitutively active Raf-l (BxB Raf). Phenotypic differences including expression of α-SMA and cell morphology between Raf-l transfectants and normal cells were assessed. Results PDGF stimulated MC proliferation from 24 to 120 hours. Expression of α-SMA was enhanced from 6 to 48 hours stimulation, but was inhibited about 50% after 72 hours stimulation. PDGF did not influence JNK activity. PDGF-induced level of JNK activity and enhanced expression of α-SMA were not influenced by treatment with MEK-1 antagonist PD98059. In the BxB-Raf expressing MC with a constitutively elevated ERK activity, JNK activity decreased by 50% and expression of α-SMA was completely absent. Less detectable microfilaments and morphologic change were found in these cells. Conclusions PDGF stimulates cell proliferation, promotes expression of α-SMA at a short period but inhibits it at persistent stimulation. PDGF regulates not only MC proliferation but also their differentiation process. These effects appear to be regulated by MAPK signaling pathways, in which activation of Raf-1 and JNK may be the critical events.

关 键 词：血小板源生长因子 信号传递 MAPK 肾小球肾炎 

分 类 号：R692.31[医药卫生—泌尿科学]