Erythropoietin upregulates angiotensin receptors in cultured rat vascular smooth muscle cells

Objective Plasma renin is not elevated in recombinant human erythropoietin (rhEPO)-induced hypertension but angiotensin converting enzyme inhibitors r educe blood pressure in both human and animal studies. Since rhEPO elevates renin and angiotensinogen messenger RNAs in angiotensin II target tissues such as the aorta, we explored the actions of rhEPO on renin-angiotensin sy stem-related gene transcription of cultured rat vascular smooth muscle cell s. Design and methods To separate direct actions of rhEPO from those mediated secondarily by potential activation of the renin-angiotensin system, vascul ar smooth muscle cells were cultured with rhEPO and enalapril to inhibit th e angiotensin converting enzyme and losartan to inhibit angiotensin II type 1 receptors, Results Vascular smooth muscle cells cultured with rhEPO (6-8 units/ml) dem onstrated elevations (40-120%) in messenger RNAs of the renin-angiotensin s ystem (renin, angiotensinogen, angiotensin receptor types 1 and 2) and incr eased levels of several messenger RNAs known to respond to angiotensin It ( transforming growth factor-p, insulin-like growth factor-II, epidermal grow th factor, c-fos and platelet-derived growth factor). In contrast, cells cu ltured in the presence of rhEPO and enalapril or losartan showed elevations of messenger RNA for only the two types of angiotensin II receptor. This i ncrease was higher than that obtained when cells were cultured with rhEPO o r either antagonist alone. The increase in specific binding of angiotensin II to cells cultured in the presence of rhEPO and enalapril or rhEPO and lo sartan paralleled the changes in receptor messenger RNA. Conclusions rhEPO exerts its primary action on vascular smooth muscle cells via an increase in angiotensin receptor messenger RNA, resulting in a para llel increase in angiotensin II receptor expression. We suggest that increa sed receptor expression secondarily mediates the expression of other renin- angiotensin system messenger RNAs, which leads to angiotensin Ii-responsive gene transcription. The elevation in angiotensin II receptors, as observed in response to rhEPO, may provide a mechanism by which other forms of reni n-dependent hypertension are initiated. (C) Lippincott Williams & Wilkins.