Abstract P338: Long Term End Organ Inflammation and Dysfunction in Mice After Angiotensin II Induced Hypertension

Abstract

Hypertension is associated with vascular and renal inflammation leading to organ dysfunction and injury. Although reduction of hypertensive stimuli or antihypertensive therapy can lower blood pressure, it is unclear if inflammation persists beyond the initial hypertensive stimulus. We sought to examine the hypothesis that a short-term hypertensive insult leads to ongoing inflammation and end organ dysfunction. C57BL/6 mice received a subcutaneous infusion of angiotensin II (490 ng/kg/min) or a sham infusion via osmotic minipumps for two weeks. The minipumps were then removed, and the mice were allowed to recover for two months. To evaluate renal function, mice received a challenge of normal saline equal to 10% of each body weight via intraperitoneal injection and the urine excreted in the subsequent 4 hours was measured. Whereas sham-treated mice excreted 88±7%, mice that had received ang II 2 months earlier excreted only 51±9% of the injected volume (p<0.05). Moreover, albuminuria was doubled in the mice that had received prior ang II infusion (0.55 ± 0.1 vs 0.26 ± 0.1 μg/ml, p < 0.05). After sacrifice, the renal and aortic samples of both groups of mice were analyzed by flow cytometry. We found that the numbers of total leukocytes (CD45 + ), total T lymphocytes (CD3 + ) and monocytes/macrophages (F4/80 + ) were 4 to 5 times higher in aortas and 45 to 70% higher in the kidneys even after two months following ang II infusion compared to sham-treated mice. We have previously shown that isolevuglandin-protein adducts in antigen presenting cells are immunogenic, and we found that these were persistently in MerTK + /CD64 + macrophages in the aorta mice that had received ang II 2 months earlier. There was also striking perivascular fibrosis in mice that had received prior ang II, but not in sham infused mice. These data indicate that a persistent inflammatory process, accompanied with renal dysfunction and aortic fibrosis continues for a prolonged period of hypertension. Efforts to ameliorate this might reduce the long-term risk renal and vascular disease.