3-nitrotyrosine and Aortic-Coarctation

Renal tubulointerstitial infiltration of activated T cells and macrophages is invariably present and plays a role in elevation of arterial pressure in nearly all animal models of hypertension (HTN). The role, if any, of elevated renal arterial pressure in the pathogenesis of this inflammatory process is uncertain. Also unclear is whether the cellular infiltration is caused by the local activation of immune cells in the kidney or a consequence of leukocyte activation in the systemic circulation.. We studied activation of peripheral blood leukocytes and cellular infiltration in the kidneys of Sprague-Dawley rats with abdominal aorta coarctation (banding) above renal arteries, which causes severe HTN proximal but not distal to coarctation.. Compared with the sham operated controls, the aorta-banded group exhibited tubulointerstitial accumulation of activated T cells, macrophages, angiotensin-II positive cells, leukocyte function-associated antigen-1 integrin expressing cells, increased nitrotyrosine abundance (a measure of oxidative stress), and increased macrophage chemoattractant protein-1 in the kidneys which are not exposed to HTN in this model. These findings were associated with the activation of the circulating leukocytes in the aorta-banded animals.. Increased baromechanical stress is not a requisite for accumulation of T cells and macrophages in the kidney in the coarctation-induced HTN and possibly in other hypertensive disorders. On the contrary, renal hypoperfusion and the consequent activation of renin-angiotensin system may mediate this process by promoting local induction of chemoattractant and inflammatory cytokines. The observed tubulointerstitial inflammation in this model is associated with leukocyte activation in the systemic circulation.

Topics: Angiotensin II; Animals; Aortic Coarctation; Chemokine CCL2; Flow Cytometry; Hydrogen Peroxide; Hypertension, Renovascular; Integrins; Kidney; Leukocytes; Lymphocytes; Macrophages; Male; Rats; Rats, Sprague-Dawley; Tyrosine

Abdominal aortic coarctation above the renal arteries leads to severe hypertension (HTN) above the stenotic site. We have recently shown marked up-regulations of endothelial nitric oxide synthase (eNOS) in heart and thoracic aorta and of neuronal NOS (nNOS) in the brain of rats with severe aortic coarctation above the renal arteries. We hypothesize that the presence of severe regional HTN in the face of marked up-regulation of NO system may be partly due to enhanced NO inactivation by reactive oxygen species (ROS) leading to functional NO deficiency.. Tissue nitrotyrosine (which is the footprint of NO interaction with ROS) was determined by Western blot in sham-operated control and aortic-banded (above renal arteries) rats three weeks postoperatively. Intra-arterial pressure and tissue nitrotyrosine (Western blot) were measured.. The banded group showed a marked rise in arterial pressure measured directly through a carotid cannula (203 +/- 9 vs. 131 +/- 2 mm Hg, P < 0.01). Compared with the sham-operated controls, the banded animals exhibited significant increases in nitrotyrosine abundance in the heart, brain, and the aorta segment above the stricture. In contrast, nitrotyrosine abundance was unchanged in the abdominal aorta segment below the stricture wherein blood pressure was not elevated.. Coarctation-induced HTN is associated with increased nitrotyrosine abundance in all tissues exposed to high arterial pressure, denoting enhanced ROS-mediated inactivation and sequestration of NO in these sites. This can, in part, account for severe regional HTN in this model. The normality of nitrotyrosine abundance in the abdominal aorta wherein blood pressure is not elevated points to the role of baromechanical factors as opposed to circulating humoral factors that were necessarily similar in both segments.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Coarctation; Baroreflex; Blotting, Western; Brain; Disease Models, Animal; Hypertension; Male; Myocardium; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tyrosine