Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

Recent evidence suggests a potential role of angiotensin II in the physiological regulation of erythropoietin (Epo) production. While the administration of exogenous angiotensin II (AII) has been used so far to study its effects, the role of endogenous AII has remained unclear.

To alter endogenous AII in humans experimentally we used furosemide bolus injection as a short-term (study 1) and dietary salt as a long-term modulator (study 2). In an open crossover design, 12 healthy male volunteers received furosemide (F) 0.5 mg kg(-1) intravenously or placebo (P) in random order (study 1). With the same design, 12 volunteers received high-salt (HS), normal-salt (NS) and low-salt (LS) diet (study 2). Plasma renin activity (PRA) was analysed along with AII. Inulin and paraaminohippurate (PAH) clearances were used to indicate glomerular filtration rate (GFR) and renal plasma flow (RPF), respectively.

While F stimulated AII and PRA and decreased GFR and RPF significantly, no concomitant alteration of Epo was observed [AUCEpo: placebo 5709 +/- 243 (% of baseline x h), furosemide: 5833 +/- 255 (% of baseline x h); 95% confidence interval (CI) -608.4, 856.0; P = 0.73]. F decreased GFR (from 103.6 +/- 4.0 to 90.6 +/- 4.8 ml min(-1) 1(-1) 73 m-2; 95% CI 1.1, 24.9; P < 0.05), but not RPF (study 1). Correspondingly, LS stimulated and HS decreased AII and PRA significantly. HS increased GFR and RPF. Again, Epo concentrations were not affected (AUCEpo: normal sodium 44 +/- 6.7 mIU x day ml(-1), low sodium 39 +/- 2.4 mIU x day ml(-1), high sodium 48.5 +/- 6.1 mIU x day ml(-1); normal salt/low salt 95% CI -11.9, 21.9, P = 0.54; normal salt/high salt 95% CI -14.4, 23.3, P = 0.63; study 2).

We conclude that, at least in the physiological setting in healthy volunteers, increased concentrations of endogenous AII may not be a major factor of Epo regulation.