Angiotensin II does not acutely reverse the reduction of proteinuria by long-term ACE inhibition

Abstract

Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II levels were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.

Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System

“…AngII caused an average 35% reduction of the ERPF in all groups (for patients with diabetes, see Figure 4B). AngII infusion induced hyperfiltration (for patients with diabetes, see Figure 4C) and a marked increase in renal vascular resistance (data not shown), as expected and described previously (31).…”

Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.

“…The mechanism of the antiproteinuric effect by ACE inhibition or AT] receptor blockade has been attributed to changes in renal hemodynamics such as reduction of glomerular capillary pressure. 4 -310 On the other hand, Heeg et al 12 have found that systemic Ang II infusion in proteinuric patients treated with long-term ACE inhibition did offset the renal hemodynamic effects of ACE inhibition, whereas Ang II infusion did not affect the antiproteinuric effect. It has also been reported that both the systemic and renal hemodynamic effects of ACE inhibitors are maximal within hours and remain stable thereafter, whereas the maximal antiproteinuric response to ACE inhibitors occurs several weeks after initiation of ACE inhibition, thereby showing the dissociation between the time course of ACE inhibitor-induced hemodynamic effects and urinary protein excretion.…”

“…4 -5 ' 10 However, recent studies have shown that the mechanism of renal protection by ACE inhibitors can also be partly attributed to unknown mechanisms other than the hemodynamic effect. 12 - 13 Furthermore, accumulating evidence shows that a local RAS exists in the kidney and supports the notion that an intrarenal RAS, independent of the circulating system, may be involved in renal pathophysiology in a paracrine or autocrine fashion. 1415 However, the possible role of this local system in renal injury is poorly understood.…”

Antihypertensive Therapy in Non-Diabetic Chronic Kidney Disease Associated with Proteinuria in Adults

“… Acute administration of angiotensin II increases intraglomerular pressure by causing renal and systemic vasoconstriction but does not reverse the antiproteinuric effect of ACE-I [4].  Nephrin is a major component of the podocyte slit pore membrane and an important contributor to the glomerular filtration barrier.…”