Angiotensin II (Ang II) has been implicated in the development of abdominal aortic aneurysm (AAA). In vascular smooth muscle cells (VSMC), Ang II activates epidermal growth factor receptor (EGFR) mediating growth promotion. We hypothesized that inhibition of EGFR prevents Ang II-dependent AAA. C57BL/6 mice were co-treated with Ang II and β-aminopropionitrile (BAPN) to induce AAA with or without treatment with EGFR inhibitor, erlotinib. Without erlotinib, 64.3% of mice were dead due to aortic rupture. All surviving mice had AAA associated with EGFR activation. Erlotinib-treated mice did not die and developed far fewer AAA. The maximum diameters of abdominal aortas were significantly shorter with erlotinib treatment. In contrast, both erlotinib-treated and non-treated mice developed hypertension. The erlotinib treatment of abdominal aorta was associated with lack of EGFR activation, endoplasmic reticulum (ER) stress, oxidative stress, interleukin-6 induction and matrix deposition. EGFR activation in AAA was also observed in humans. In conclusion, EGFR inhibition appears to protect mice from AAA formation induced by Ang II plus BAPN. The mechanism seems to involve suppression of vascular EGFR and ER stress.
Key words:peritoneal dialysis, renal anemia, darbepoetin alfa, serum albumin 〈Abstract〉 Patients with renal anemia have a narrow target range for hemoglobin levels. In some cases, it is difficult to maintain hemoglobin levels within this target range. To manage the treatment of renal anemia in patients undergoing peritoneal dialysis, we examined the relationship between the weekly average darbepoetin alfa dose and hemoglobin levels. The weekly average darbepoetin alfa dose for 15 weeks before a blood test exhibited the highest correlation with hemoglobin levels. Of 39 patients, 22 exhibited a significant positive correlation among / these parameters(p<0.05). On the other hand, the number of patients with serum albumin levels≦3.0 g/dL was significantly higher in the group that exhibited no correlation as compared to the group that did(p=0.01). Using the weekly average darbepoetin alfa dose over 15 weeks, we can estimate the weekly average dose necessary for maintaining hemoglobin levels within the target range. This study demonstrates that examining the relationship between the weekly average darbepoetin alfa dose and hemoglobin levels is useful for determining the ideal dose of darbepoetin alfa in patients undergoing peritoneal dialysis.
A metalloprotease, ADAM17, mediates EGF receptor (EGFR) activation in vascular smooth muscle cells (VSMC) by angiotensin II (Ang II) leading to hypertrophy. dnADAM17 prevents vascular neointimal hyperplasia. To test if vascular ADAM17 silencing has any therapeutic potential against hypertension, we evaluated Ang II-induced end-organ damage as well as hypertension in ADAM17 flox/flox mice bred with sm22α Cre mice (Cre+/-). Upon Ang II infusion (1 μg/kg/min) for 2 weeks, control Cre-/- mice showed phenotypes of cardiac hypertrophy; HW/BW ratio (mg/g: 12.1±1.6 vs 6.2±0.4 p<0.05 n=8), cardiac echo (LVPWd mm: 0.96±0.05 vs 0.75±0.04, p<0.05) and plasma BNP (pg/mL: 1.94±0.36 vs 0.07±0.2, p<0.05) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, these phenotypic changes were attenuated in VSMC ADAM17 silenced Cre+/- hearts with Ang II infusion; HW/BW ratio (7.0±0.8 vs 6.6±0.7 n=5), cardiac echo (LVPWd: 0.71±0.09 vs 0.65±0.09) and BNP (0.52±0.19 vs 0.03±0.003, p<0.05) compared with saline infusion. Control Cre-/- with Ang II infusion also demonstrated renal dysfunction assessed by BUN (mg/dL: 40.1±2.9 vs 23.0±2.8 p<0.05 n=6) compared with saline infusion, which was partially prevented in Cre+/- mice (30.4±2.5 vs 21.3±4.0 p<0.05). Renal fibrosis observed in Cre-/- with Ang II infusion was also attenuated in Cre+/- with Ang II infusion. However, Ang II induced hypertension in both Cre-/- and +/- mice assessed by radiotelemetry (MAP mmHg: 160±6 vs 155±7). Ang II infusion in Cre-/- enhanced ADAM17 and phospho-Tyr1068 EGFR staining in vasculatures of heart and kidney, whereas Ang II infused Cre+/- had diminished phospho-Tyr1068 EGFR staining and no ADAM17 staining in the vasculatures. qPCR analyses of cardiac ADAM17 mRNA in hearts further support these findings. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused Cre-/- compared with Ang II-infused Cre+/-. These data suggest that vascular ADAM17/EGFR axis is critical for end organ damage via induction of ER/oxidative stress independent from blood pressure regulation.
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