期刊
CIRCULATION RESEARCH
卷 89, 期 12, 页码 1138-1146出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh2401.101270
关键词
angiotensinogen; angiotensin; intracrine; intracellular; receptor blocker
To differentiate the relative effects of nuclear and cell surface angiotensin IT (Ang IT) receptors, we mutated the angiotensinogen cDNA by removing the signal sequence-encoding region to produce a nonsecreted form of angiotensinogen [Ang(-S)Exp], Rat hepatoma cells (which produce renin and angiotensin-converting enzyme mRNAs) Were stably transfected with Ang(-S)Exp/pSVL (or a corresponding control) expression plasmid, and mitotic indices were measured for stably transfected cell lines. Experimental clonal cell lines demonstrate an average of 33 +/-4.4% (P <0.001) increase in percentage-labeled nuclei compared with control cell lines. The mitogenic effect is blocked by 10(-6) mol/L losartan and by I mu mol/L renin antisense phosphorothioate oligomers but not by 10(6) mol/L candesartan. In addition. phenylarsine oxide, which blocks angiotensin receptor internalization, abolishes the losartan inhibitory effect. suggesting that after cell-surface receptor-mediated endocytosis, losartan blocks Ang II nuclear receptors, PDGF mRNA levels are elevated 2.2-fold in Ang(-S)Exp transfected cell lines; addition of anti-PDGF antibodies to the culture medium partially blocks the mitogenic effect of Ang(-S)Exp, while anti-Ang II antibodies have no effect. These results suggest that the Ang(-S)Exp growth effect is due, in part. to autocrine/paracrine stimulation by secreted PDGF after Ang II/Ang II receptor intracellular interactions. We further demonstrate that these cells produce the alternative renin transcript. renin IA, which apparently lacks a signal sequence and is maintained intracellularly. Collectively, these studies of cultured cells suggest that some cell types may possess components of the renin-angiotensin system that permit intracellular processing of angiotensinogen to Ang II and that Ang II generated intracellularly may be mitogenic.
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