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RECEPTORS AND SIGNAL TRANSDUCTION

Intracellular ANG II directly induces in vitro transcription of TGF-β1, MCP-1, and NHE-3 mRNAs in isolated rat renal cortical nuclei via activation of nuclear AT_1a receptors

¹Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit; and ²Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan

Submitted 18 September 2007 ; accepted in final form 1 February 2008

The present study tested the hypothesis that intracellular ANG II directly induces transcriptional effects by stimulating AT_1a receptors in the nucleus of rat renal cortical cells. Intact nuclei were freshly isolated from the rat renal cortex, and transcriptional responses to ANG II were studied using in vitro RNA transcription assays and semiquantitative RT-PCR. High-power phase-contrast micrographs showed that isolated nuclei were encircled by an intact nuclear envelope and stained strongly by the DNA marker 4',6-diamidino-2-phenylindole, but not by the membrane or endosomal markers. Fluorescein isothiocyanate-labeled ANG II and [¹²⁵I]Val⁵-ANG II binding confirmed the presence of ANG II receptors in the nuclei with a predominance of AT₁ receptors. RT-PCR showed that AT_1a mRNA expression was threefold greater than AT_1b receptor mRNAs in these nuclei. In freshly isolated nuclei, ANG II increased in vitro [-³²P]CTP incorporation in a concentration-dependent manner, and the effect was confirmed by autoradiography and RNA electrophoresis. ANG II markedly increased in vitro transcription of mRNAs for transforming growth factor-β1 by 143% (P < 0.01), macrophage chemoattractant protein-1 by 89% (P < 0.01), and the sodium and hydrogen exchanger-3 by 110% (P < 0.01). These transcriptional effects of ANG II on the nuclei were completely blocked by the AT₁ receptor antagonist losartan (P < 0.01). By contrast, ANG II had no effects on transcription of angiotensinogen and glyceraldehyde-3-phosphate dehydrogenase mRNAs. Because these transcriptional effects of ANG II in isolated nuclei were induced by ANG II in the absence of cell surface receptor-mediated signaling and completely blocked by losartan, we concluded that ANG II may directly stimulate nuclear AT_1a receptors to induce transcriptional responses that are associated with tubular epithelial sodium transport, cellular growth and hypertrophy, and proinflammatory cytokines.

angiotensin II; in vitro transcription; kidney; nucleus; reverse transcription-polymerase chain reaction; sodium transport

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