Published online before print November 2, 2006, doi: 10.1161/01.RES.0000251700.00994.0d
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 17, 2006
Revised on October 9, 2006
Accepted on October 25, 2006
A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein
Jan H. Schefe ;
From the Center for Cardiovascular Research/Institute of Pharmacology (J.H.S., M.M., J.R., T.U., H.F.-K.), Department of Anesthesiology and Intensive Care Medicine (M.M.), and Center for Cardiovascular Research (K.E., P.R.), Charité-Universitätsmedizin Berlin, Germany; Max Planck Institute for Molecular Genetics (K.E., P.R.), Berlin, Germany; and Cancer Biology and Genetics Program (R.M.H., P.P.P.), Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York.
* To whom correspondence should be addressed. E-mail: heiko.funke-kaiser{at}charite.de.
A human renin/prorenin receptor (RER) has recently been cloned. To gain insight into the molecular function of the RER, we studied its signal transduction mechanisms. Initially, we found a ubiquitous and intracellular expression pattern of the human RER. Consistently, we observed several transcriptional start sites and a high promoter activity of the human RER. We could identify the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the RER by yeast 2-hybrid screening and coimmunoprecipitation. Coimmunoprecipitation experiments also indicated homodimerization of the RER. On activation of the RER by renin, PLZF is translocated into the nucleus and represses transcription of the RER itself, thereby creating a very short negative feedback loop, but activates transcription of the p85
subunit of the phosphatidylinositol-3 kinase (PI3K-p85). Small interfering RNA against the RER abolished these effects. A PLZF cis element in the RER promoter was identified by site-directed mutagenesis and electrophoretic mobility-shift assay; renin stimulation caused a 6-fold recruitment of PLZF to this promoter region as shown by chromatin immunoprecipitation. Moreover, renin stimulation of rat H9c2 cardiomyoblasts induced an increase of cell number and a decrease of apoptosis. These effects were partly abolished by PI3K inhibition and completely abrogated by small interfering RNA against PLZF. Finally, experiments in PLZF knockout mice confirmed the role of PLZF as an upstream regulator of RER and PI3K-p85. Our data demonstrate the existence of a novel signal transduction pathway involving the ligand renin, RER, and the transcription factor PLZF, which is of physiological and putative pathophysiological relevance.
Key words: renin receptor • PLZF • ChIP • signal transduction
Related Article:
- On the Pathophysiological Implications of an Intracellular Renin Receptor
- Walmor C. De Mello
Circ. Res. 2006 99: 1285-1286.[Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  A. Naray-Fejes-Toth, C. Boyd, and G. Fejes-Toth Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein Am J Physiol Renal Physiol, July 1, 2008; 295(1): F18 - F26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Feldman, L. Jin, H. Xuan, A. Contrepas, Y. Zhou, R. L. Webb, D. N. Mueller, S. Feldt, F. Cumin, W. Maniara, et al. Effects of Aliskiren on Blood Pressure, Albuminuria, and (Pro)Renin Receptor Expression in Diabetic TG(mRen-2)27 Rats Hypertension, July 1, 2008; 52(1): 130 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Werner and M. Bohm Review: The therapeutic role of RAS blockade in chronic heart failure Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 167 - 177. [Abstract] [PDF]
|
|
|
|
 |
|
 W. W. Batenburg, R. J.A. de Bruin, J. M.G. van Gool, D. N. Muller, M. Bader, G. Nguyen, and A. H. J. Danser Aliskiren-Binding Increases the Half Life of Renin and Prorenin in Rat Aortic Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1151 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kuipers, P. van der Harst, G. Navis, L. van Genne, F. Morello, W. H. van Gilst, D. J. van Veldhuisen, and R. A. de Boer Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System Hypertension, June 1, 2008; 51(6): 1442 - 1448. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Nguyen and A. H. J. Danser Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents Exp Physiol, May 1, 2008; 93(5): 557 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Campbell Critical Review of Prorenin and (Pro)renin Receptor Research Hypertension, May 1, 2008; 51(5): 1259 - 1264. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Feldt, U. Maschke, R. Dechend, F. C. Luft, and D. N. Muller The Putative (Pro)renin Receptor Blocker HRP Fails to Prevent (Pro)renin Signaling J. Am. Soc. Nephrol., April 1, 2008; 19(4): 743 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C Luft The Bothrops legacy: Vasoactive peptides from Brazil Journal of Renin-Angiotensin-Aldosterone System, March 1, 2008; 9(1): 57 - 64. [PDF]
|
|
|
|
|
|
B. Peters and J. Peters Absence of prorenin-induced glomerulosclerosis in cyp1a1ren-2 transgenic rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2008; 9(1_suppl): S4 - S4. [PDF]
|
|
|
|
 |
|
 R. N. Re and J. L. Cook The Basis of an Intracrine Pharmacology J. Clin. Pharmacol., March 1, 2008; 48(3): 344 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Feldt, W. W. Batenburg, I. Mazak, U. Maschke, M. Wellner, H. Kvakan, R. Dechend, A. Fiebeler, C. Burckle, A. Contrepas, et al. Prorenin and Renin-Induced Extracellular Signal-Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide Hypertension, March 1, 2008; 51(3): 682 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Muller, B. Klanke, S. Feldt, N. Cordasic, A. Hartner, R. E. Schmieder, F. C. Luft, and K. F. Hilgers (Pro)Renin Receptor Peptide Inhibitor "Handle-Region" Peptide Does Not Affect Hypertensive Nephrosclerosis in Goldblatt Rats Hypertension, March 1, 2008; 51(3): 676 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Campbell Interpretation of Plasma Renin Concentration in Patients Receiving Aliskiren Therapy Hypertension, January 1, 2008; 51(1): 15 - 18. [Full Text] [PDF]
|
|
|
|
|
|
M. Bader Spotlight on Renin: The second life of the (Pro)renin receptor Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 205 - 208. [PDF]
|
|
|
|
|
|
E. D. Frohlich The Salt Conundrum: A Hypothesis Hypertension, July 1, 2007; 50(1): 161 - 166. [Full Text] [PDF]
|
|
|
|
|
|
F. Suzuki Nonproteolytic activation of prorenin by the (pro)renin receptor is blocked by decoy peptide Journal of Renin-Angiotensin-Aldosterone System, June 1, 2007; 8(2): 101 - 103. [PDF]
|
|
|
|
 |
|
 A. H. Jan Danser, W. W. Batenburg, and J. H. M. van Esch Prorenin and the (pro)renin receptor--an update Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1288 - 1292. [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. De Mello On the Pathophysiological Implications of an Intracellular Renin Receptor Circ. Res., December 8, 2006; 99(12): 1285 - 1286. [Full Text] [PDF]
|
|