(Circulation. 1999;99:2185-2191.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats
From INSERM U 489, Paris (P.-L.T., C.C., R.A., J.-C.D.); IURC, Montpellier (D.C.); INSERM U 402, Paris (L.F.); and Service de Physiologie, CHU Saint-Antoine, Paris (J.-C.D.), France.
Correspondence to Jean-Claude Dussaule, MD, PhD, Service de Physiologie, CHU Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. E-mail jean-claude.dussaule{at}sat.ap-hop-paris.fr
Background—The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process.
Methods and Results—Treatment of rats for 4 weeks with the NO
synthase inhibitor
N
-nitro-L-arginine methyl ester
(L-NAME) 50 mg · kg-1 · d-1
increased systolic blood pressure to 159±12 mm Hg. In
animals treated with L-NAME, histological evaluation of
renal sections revealed an increased formation of extracellular matrix
(Masson's trichrome), and specifically of collagens (Sirius red). A
part of this fibrosis was attributed to abnormal collagen I presence,
because mRNA expression of the collagen I 
1 chain (reverse
transcription–polymerase chain reaction) and procollagen I formation
(radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the
renal resistance vessels of hypertensive animals. In subsequent
experiments, we examined whether ET-1 was involved in activation of
collagen I formation. mRNA expression (RNase protection assay) of
preproET-1 and ET-1 content (radioimmunoassay) were 10-fold and 3-fold
increased, respectively, in renal microvessels of rats treated with
L-NAME. Interestingly, in these vessels, ET-1
(immunostaining) was colocalized with sudanophilic
lesions. Bosentan, an ET receptor antagonist (20 mg
· kg-1 · d-1), coadministered with
L-NAME canceled the increased mRNA expression and synthesis of collagen
I and attenuated the severity of renal vascular lesions without
affecting L-NAME–induced high blood pressure.
Conclusions—These data demonstrate that ET-1 synthesis is increased in renal microvessels when NO production is suppressed. In this model of hypertension, ET-1 is a major activator of collagen I formation in renal resistance vessels and participates in the development of renal fibrosis without affecting systolic blood pressure.
Key Words: hypertension • nitric oxide • endothelin • kidney • fibrosis
This article has been cited by other articles:
 |
|
 |
|
  B. S. Fleenor and D. K. Bowles Exercise training decreases the size and alters the composition of the neointima in a porcine model of percutaneous transluminal coronary angioplasty (PTCA) J Appl Physiol, September 1, 2009; 107(3): 937 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Helle, C. Jouzel, C. Chadjichristos, S. Placier, M. Flamant, D. Guerrot, H. Francois, J.-C. Dussaule, and C. Chatziantoniou Improvement of renal hemodynamics during hypertension-induced chronic renal disease: role of EGF receptor antagonism Am J Physiol Renal Physiol, July 1, 2009; 297(1): F191 - F199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chansel, M. Ciroldi, S. Vandermeersch, L. F Jackson, A.-M. Gomez, D. Henrion, D. C. Lee, T. M. Coffman, S. Richard, J.-C. Dussaule, et al. Heparin binding EGF is necessary for vasospastic response to endothelin FASEB J, September 1, 2006; 20(11): 1936 - 1938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Placier, J.-J. Boffa, J.-C. Dussaule, and C. Chatziantoniou Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice Nephrol. Dial. Transplant., April 1, 2006; 21(4): 881 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Sutherland, M. I. Nataatmadja, P. J. Walker, L. Cuttle, R. B. Garlick, and M. J. West Vascular Remodeling in the Internal Mammary Artery Graft and Association With In Situ Endothelin-1 and Receptor Expression Circulation, March 7, 2006; 113(9): 1180 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. An, R. Boyd, Y. Wang, X. Qiu, and H. D. Wang Endothelin-1 expression in vascular adventitial fibroblasts Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H700 - H708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chatziantoniou and J.-C. Dussaule Insights into the mechanisms of renal fibrosis: is it possible to achieve regression? Am J Physiol Renal Physiol, August 1, 2005; 289(2): F227 - F234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ying, M. Flamant, S. Vandermeersch, J.-J. Boffa, C. Chatziantoniou, J.-C. Dussaule, and D. Chansel Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide-Deficient Rats Hypertension, November 1, 2003; 42(5): 937 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Boffa, Y. Lu, S. Placier, A. Stefanski, J.-C. Dussaule, and C. Chatziantoniou Regression of Renal Vascular and Glomerular Fibrosis: Role of Angiotensin II Receptor Antagonism and Matrix Metalloproteinases J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1132 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Seccia, A. S. Belloni, R. Kreutz, M. Paul, G. G. Nussdorfer, A. C. Pessina, and G. P. Rossi Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II J. Am. Coll. Cardiol., February 19, 2003; 41(4): 666 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kataoka, K. Egashira, S. Inoue, M. Takemoto, W. Ni, M. Koyanagi, S. Kitamoto, M. Usui, K. Kaibuchi, H. Shimokawa, et al. Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats Hypertension, February 1, 2002; 39(2): 245 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Fakhouri, S. Placier, R. Ardaillou, J.-C. Dussaule, and C. Chatziantoniou Angiotensin II Activates Collagen Type I Gene in the Renal Cortex and Aorta of Transgenic Mice through Interaction with Endothelin and TGF-{beta} J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2701 - 2710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W Barolet, S. Babaei, R. Robinson, P. Picard, W. Tsui, N. Nili, F. Mohamed, O. Ornatsky, J. D Sparkes, D. J Stewart, et al. Administration of exogenous endothelin-1 following vascular balloon injury: early and late effects on intimal hyperplasia Cardiovasc Res, December 1, 2001; 52(3): 468 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kaikita, A. B. Fogo, L. Ma, J. A. Schoenhard, N. J. Brown, and D. E. Vaughan Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition Circulation, August 14, 2001; 104(7): 839 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ferrini, T. R. Magee, D. Vernet, J. Rajfer, and N. F. González-Cadavid Aging-Related Expression of Inducible Nitric Oxide Synthase and Markers of Tissue Damage in the Rat Penis Biol Reprod, March 1, 2001; 64(3): 974 - 982. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. Casellas, A. Herizi, A. Artuso, A. Mimran, and B. Jover Candesartan prevents L-NAME-induced cardio-renal injury in spontaneously hypertensive rats beyond hypotensive effects Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S84 - S90. [Abstract] [PDF]
|
|
|
|
|
|
J.-J. Boffa, Ying Lu, J.-C. Dussaule, and C. Chatziantoniou Improvements of renal lesions and function by angiotensin and endothelin receptor antagonism in nitric oxide-deficient rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S211 - S216. [Abstract] [PDF]
|
|
|
|
|
|
J.-J. Boffa, P.-L. Tharaux, J.-C. Dussaule, and C. Chatziantoniou Regression of Renal Vascular Fibrosis by Endothelin Receptor Antagonism Hypertension, February 1, 2001; 37(2): 490 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Fujihara, D. M. Avancini Costa Malheiros, I. de Lourdes Noronha, G. De Nucci, and R. Zatz Mycophenolate Mofetil Reduces Renal Injury in the Chronic Nitric Oxide Synthase Inhibition Model Hypertension, January 1, 2001; 37(1): 170 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Koyanagi, K. Egashira, S. Kitamoto, W. Ni, H. Shimokawa, M. Takeya, T. Yoshimura, and A. Takeshita Role of Monocyte Chemoattractant Protein-1 in Cardiovascular Remodeling Induced by Chronic Blockade of Nitric Oxide Synthesis Circulation, October 31, 2000; 102(18): 2243 - 2248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lepailleur-Enouf, O. Valdenaire, M. Philippe, M. Jandrot-Perrus, and J.-B. Michel Thrombin induces endothelin expression in arterial smooth muscle cells Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1606 - H1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Boffa, P.-L. Tharaux, S. Placier, R. Ardaillou, J.-C. Dussaule, and C. Chatziantoniou Angiotensin II Activates Collagen Type I Gene in the Renal Vasculature of Transgenic Mice During Inhibition of Nitric Oxide Synthesis : Evidence for an Endothelin-Mediated Mechanism Circulation, November 2, 1999; 100(18): 1901 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Larouche and E. L. Schiffrin Cardiac Microvasculature in DOCA-Salt Hypertensive Rats : Effect of Endothelin ETA Receptor Antagonism Hypertension, October 1, 1999; 34(4): 795 - 801. [Abstract] [Full Text] [PDF]
|
|