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NDT Advance Access originally published online on July 6, 2004
Nephrology Dialysis Transplantation 2004 19(9):2184-2191; doi:10.1093/ndt/gfh388
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Nephrol Dial Transplant Vol. 19 No. 9 © ERA-EDTA 2004; all rights reserved

Original Article

Angiotensin II activates the human renin promoter in an in vitro model: the role of c-Jun-N-terminal kinase

Tamás Terebessy1,2, András Masszi1,2, Attila Fintha1,2, Attila Sebe1,2, Tamás Huszár1,2,3, László Rosivall1,2 and István Mucsi1,2,4

1 Department of Pathophysiology, Faculty of Medicine, Semmelweis University, Budapest, 2 Hungarian Academy of Sciences and Semmelweis University Nephrology Research Group, 3 Department of Oral- and Maxillofacial Surgery, Faculty of Dentistry, Semmelweis University, Budapest and 4 1st Department of Medicine; Faculty of Medicine, Semmelweis University, Budapest, Hungary

Correspondence and offprint requests to: Istvan Mucsi, MD, PhD, 1st Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest. Current mailing address: 21 Mayfair Avenue, Apt 414, Toronto, Ontario, M5N 2N5, Canada. Email: mucsist{at}net.sote.hu

Background. Angiotensin II (Ang II) down-regulates renin expression in juxtaglomerular cells, however, recent experimental evidence obtained in transgenic mice suggested that Ang II may ‘paradoxically’ increase transcriptional activity of the proximal renin promoter.

Methods. To dissect signalling mechanisms contributing to the up-regulation of the proximal renin promoter by Ang II, porcine proximal tubular cells stably expressing the rabbit AT1 receptor (LLC-PK/AT1) were transiently transfected with a luciferase reporter construct containing the 582 bp long piece of the human renin promoter. Activation of mitogen-activated protein kinases (MAPK) was detected by western blotting using phospho-MAPK-specific antibodies.

Results. Ang II dose-dependently stimulated the transcriptional activity of the human renin promoter (10–7 M Ang II: 3.50±1.25-fold stimulation). In these cells Ang II activated both extracellular signal-regulated kinase (ERK) and the c-Jun-N-terminal kinase (JNK). Inhibition of the ERK cascade did not reduce the stimulation of the renin promoter by Ang II, however, two expression vectors designed to inhibit the JNK pathway, the dominant negative JNK and the Jun-kinase interacting peptide inhibited the fold stimulation induced by Ang II (2.75±0.69 vs 1.6±0.23 and 1.8±0.34, respectively; P<0.01). Furthermore, genistein, a tyrosine kinase inhibitor, blocked the effect of Ang II both on the JNK and the promoter activation.

Conclusion. Ang II may have a stimulatory effect on the proximal renin promoter in proximal tubular cells and this effect is mediated by tyrosine kinases and the JNK cascade.

Keywords: angiotensin II; human renin promoter; mitogen-activated protein kinases; renal tubular cell; transcriptional regulation; tyrosine kinases


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