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

Angiotensin (Ang) II-induced organ damage has fascinated students of hypert ension since the work of Wilson and Byrom. We are investigating a double tr ansgenic rat (dTGR) model, in which rats transgenic for the human angiotens inogen and renin genes are crossed. These rats develop moderately severe hy pertension but die of end-organ cardiac and renal damage by week 7. The hea rt 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 a re found on circulating leukocytes, Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-b eta and deposition of extracellular matrix proteins follows, which is accom panied by fibrinoid vasculitis in small vessels of the heart and kidneys. A ngiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowe red blood pressure and shifted pressure natriuresis partially leftward by d ifferent mechanisms. When combined, they normalized blood pressure, pressur e natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy complete ly. Endothelin receptor blockade had no influence on blood pressure but pro tected from vasculopathy and improved survival. We show evidence that Ang I I stimulates oxidative stress directly or indirectly via endothelin 1 and t hat NF kappa B is upregulated in this model. We speculate that the transcri ption factors NF kappa B and AP-1 are involved with initiating chemokine an d cytokine expression, leading to the above cascade. The unique model and o ur pharmacological probes will enable us to test these hypotheses.