Hypertension-induced end-organ damage : A new transgenic approach to an old problem.

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.

[1]  D. Ganten,et al.  Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes. , 1999, Journal of the American Society of Nephrology : JASN.

[2]  D. Ganten,et al.  Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. , 1999, Hypertension.

[3]  D. Ganten,et al.  Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes. , 1998, Journal of the American Society of Nephrology : JASN.

[4]  C. Sobey,et al.  Evidence that macrophages in atherosclerotic lesions contain angiotensin II. , 1998, Circulation.

[5]  K. Mihara,et al.  Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. , 1998, Circulation.

[6]  B. Lévy,et al.  Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat. , 1998, Hypertension.

[7]  A. Tedgui,et al.  Signal transduction of mechanical stresses in the vascular wall. , 1998, Hypertension.

[8]  A. Danser,et al.  Angiotensin production by the heart: a quantitative study in pigs with the use of radiolabeled angiotensin infusions. , 1998, Circulation.

[9]  K. Hirata,et al.  Stimulatory interaction between vascular endothelial growth factor and endothelin-1 on each gene expression. , 1998, Hypertension.

[10]  M. Ishida,et al.  Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role in activation of JNK. , 1998, Circulation research.

[11]  R. Alexander,et al.  p38 Mitogen-activated Protein Kinase Is a Critical Component of the Redox-sensitive Signaling Pathways Activated by Angiotensin II , 1998, The Journal of Biological Chemistry.

[12]  L. Mazzolai,et al.  Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. , 1998, Hypertension.

[13]  G. Cerasola,et al.  Changes of plasma endothelin and growth factor levels, and of left ventricular mass, after chronic AT1-receptor blockade in human hypertension. , 1998, American journal of hypertension.

[14]  S. Schwartz,et al.  Vitronectin decreases microvascular endothelial cell apoptosis , 1998, Journal of cellular physiology.

[15]  K.,et al.  Regulation of glomerular TGF-beta expression in the contralateral kidney of two-kidney, one-clip hypertensive rats. , 1998, Journal of the American Society of Nephrology : JASN.

[16]  H Ishii,et al.  Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Raschack,et al.  Nephroprotection of an ETA-Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats , 1998 .

[18]  HitoshiTakagi,et al.  Angiotensin II Potentiates Vascular Endothelial Growth Factor–Induced Angiogenic Activity in Retinal Microcapillary Endothelial Cells , 1998 .

[19]  David A Tulis,et al.  Flow-induced arterial remodeling in rat mesenteric vasculature. , 1998, American journal of physiology. Heart and circulatory physiology.

[20]  M. Daemen,et al.  Mitogenic effect of angiotensin II on rat carotid arteries and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous basic fibroblast growth factor. , 1998, Circulation research.

[21]  R. Hamdy,et al.  Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. , 1998, Biochimica et biophysica acta.

[22]  B. Brenner,et al.  Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. , 1998, Journal of the American Society of Nephrology : JASN.

[23]  Jennifer L Hall,et al.  Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease , 1998, Nature Medicine.

[24]  T. Shimokama,et al.  The Tsukuba hypertensive mouse (transgenic mouse carrying human genes for both renin and angiotensinogen) as a model of human malignant hypertension: development of lesions and morphometric analysis , 1998, Virchows Archiv.

[25]  S. Schwartz Cell death and the caspase cascade. , 1998, Circulation.

[26]  K. Maehara,et al.  Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. , 1998, Circulation.

[27]  J. Ménard,et al.  Local angiotensin II generation in the rat heart: role of renin uptake. , 1998, Circulation research.

[28]  L. Raij Nitric oxide in hypertension: relationship with renal injury and left ventricular hypertrophy. , 1998, Hypertension.

[29]  S. Chien,et al.  Effects of mechanical forces on signal transduction and gene expression in endothelial cells. , 1998, Hypertension.

[30]  M. Raschack,et al.  Nephroprotection of an ET(A)-receptor blocker (LU 135252) in salt-loaded uninephrectomized stroke-prone spontaneously hypertensive rats. , 1998, Hypertension.

[31]  W. R. Taylor,et al.  Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats. , 1997, Hypertension.

[32]  Shokei Kim,et al.  Involvement of angiotensin II in cardiovascular and renal injury: effects of an AT1‐receptor antagonist on gene expression and the cellular phenotype , 1997, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[33]  T. Aw,et al.  Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells. , 1997, Circulation research.

[34]  S. Anderson Role of local and systemic angiotensin in diabetic renal disease. , 1997, Kidney international. Supplement.

[35]  M. Mann,et al.  Future horizons in cardiovascular molecular therapeutics. , 1997, The American journal of cardiology.

[36]  P. Jones,et al.  Regulation of Tenascin-C, a Vascular Smooth Muscle Cell Survival Factor that Interacts with the αvβ3 Integrin to Promote Epidermal Growth Factor Receptor Phosphorylation and Growth , 1997, The Journal of cell biology.

[37]  G. Jennings,et al.  Angiotensin-converting enzyme inhibition abolishes medial smooth muscle PDGF-AB biosynthesis and attenuates cell proliferation in injured carotid arteries: relationships to neointima formation. , 1997, Circulation.

[38]  T. Lüscher,et al.  Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist. , 1997, Circulation.

[39]  G. Wolf,et al.  Renal tubular hypertrophy induced by angiotensin II. , 1997, Seminars in nephrology.

[40]  F. Thaiss,et al.  Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. , 1997, The Journal of clinical investigation.

[41]  R. Prewitt,et al.  Myogenic tone attenuates pressure-induced gene expression in isolated small arteries. , 1997, Hypertension.

[42]  E. Schiffrin,et al.  Clinical significance of endothelin in cardiovascular disease , 1997, Current opinion in cardiology.

[43]  F. Luft,et al.  Leukocyte infiltration and ICAM-1 expression in two-kidney one-clip hypertension. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[44]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[45]  J. Egido,et al.  Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. , 1997, Circulation.

[46]  S. Rajagopalan,et al.  Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. , 1997, Circulation.

[47]  V. Muzykantov,et al.  Effects of chronic arterial hypertension on constitutive and induced intercellular adhesion molecule-1 expression in vivo. , 1997, Hypertension.

[48]  R. Nerem,et al.  Cyclic strain induces an oxidative stress in endothelial cells. , 1997, The American journal of physiology.

[49]  D. Vaughan,et al.  Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. , 1997, Kidney international.

[50]  A. Barakat,et al.  Spatial relationships in early signaling events of flow-mediated endothelial mechanotransduction. , 1997, Annual review of physiology.

[51]  J. Ménard,et al.  High human renin hypertension in transgenic rats. , 1997, Hypertension.

[52]  K. Hilgers,et al.  Experimental studies on the role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in hypertensive nephrosclerosis. , 1996, Hypertension.

[53]  F. Luft,et al.  Effects of intracellular angiotensin II in vascular smooth muscle cells. , 1996, Circulation research.

[54]  D. Heudes,et al.  Endothelin antagonism in end-organ damage of spontaneously hypertensive rats. Comparison with angiotensin-converting enzyme inhibition and calcium antagonism. , 1996, Hypertension.

[55]  D. Harrison,et al.  Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[56]  F. Luft,et al.  Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat. , 1996, Kidney international.

[57]  S. Orlov,et al.  Apoptosis and vascular wall remodeling in hypertension. , 1996, Canadian journal of physiology and pharmacology.

[58]  C. Sen,et al.  Antioxidant and redox regulation of gene transcription , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[59]  G. Remuzzi,et al.  Malignant vascular disease of the kidney: nature of the lesions, mediators of disease progression, and the case for bilateral nephrectomy. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[60]  M. Marrero,et al.  Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. , 1996, Hypertension.

[61]  C. Sigmund,et al.  Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. , 1996, The Journal of clinical investigation.

[62]  D. Ganten,et al.  Effects of human renin in the vasculature of rats transgenic for human angiotensinogen. , 1995, Hypertension.

[63]  W. Mello Influence of Intracellular Renin on Heart Cell Communication , 1995 .

[64]  R. Carey,et al.  Renal Interstitial Fluid Angiotensin: Modulation by Anesthesia, Epinephrine, Sodium Depletion, and Renin Inhibition , 1995 .

[65]  R. Alexander Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. , 1995, Hypertension.

[66]  W. D. De Mello Influence of intracellular renin on heart cell communication. , 1995, Hypertension.

[67]  T. Schaberg,et al.  Monocyte infiltration and c-fms expression in hearts of spontaneously hypertensive rats. , 1995, Hypertension.

[68]  F. Luft,et al.  Early interstitial changes in hypertension-induced renal injury. , 1993, Hypertension.

[69]  D. Ganten,et al.  Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Y. Hirata,et al.  Induction of Endothelin‐1 Gene by Angiotensin and Vasopressin in Endothelial Cells , 1992, Hypertension.

[71]  M. Katsuki,et al.  Tissue-specific expression of the human renin gene in transgenic mice. , 1989, Biochemical and biophysical research communications.

[72]  R. Roman,et al.  Characterization of a new model for the study of pressure-natriuresis in the rat. , 1985, The American journal of physiology.

[73]  P. Khairallah,et al.  Effects of Angiotensin II and Some Analogues on Vascular Permeability in the Rabbit , 1972, Circulation research.

[74]  P. Kincaid‐smith,et al.  Structural and Ultrastructural Alterations in Mesenteric and Renal Arterioles Following Infusion of Vaso-Active Agents , 1972 .

[75]  A. W. Asscher,et al.  A Vascular Permeability Factor of Renal Origin , 1963, Nature.

[76]  A. Clark Eriochrome Black T as a Protein Dye , 1962, Nature.

[77]  Clifford Wilson,et al.  RENAL CHANGES IN MALIGNANT HYPERTENSION , 1939 .

[78]  Clifford Wilson,et al.  RENAL CHANGES IN MALIGNANT HYPERTENSION: EXPERIMENTAL EVIDENCE , 1939 .

[79]  H. Goldblatt,et al.  STUDIES ON EXPERIMENTAL HYPERTENSION I. THE PRODUCTION OF PERSISTENT ELEVATION OF SYSTOLIC BLOOD PRESSURE BY MEANS OF RENAL ISCHEMIA , 1934 .