New roles for renin and prorenin in heart failure and cardiorenal crosstalk

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure–associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1–7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways

Determinants of renal actions of atrial natriuretic peptide. Lack of effect of atrial natriuretic peptide on pressure-induced vasoconstriction.

We have previously demonstrated that atrial natriuretic peptide (ANP) completely reverses norepinephrine-induced afferent arteriolar (AA) vasoconstriction. In the present study we characterized the effects of ANP on pressure-induced vasoconstriction of AA. Chronic unilateral hydronephrosis was induced to facilitate direct visualization of the renal microcirculation. Hydronephrotic kidneys were perfused in vitro, and AA diameters were measured during stepwise alterations in renal arterial pressure. Increasing renal arterial pressure from 80 to 180 mm Hg decreased AA diameter by 22±2% (from 18.5±1.0 to 14.4±1.0 μm, p<0.005). In the presence of 100 nM ANP [human ANP-(4–28)], AA vasoconstricted by 23±4%, indicating that ANP failed to modify the pressure-induced AA vasoconstriction. Furthermore, both nitroprusside (10 μM) and 8-bromoguanosine 3′:5′-cyclic monophosphate (30 μM) only partially inhibited pressure-induced AA vasoconstriction (31±5% and 47±7%, respectively), whereas these vasodilators completely abolished norepinephrine-induced AA vasoconstriction. In contrast, nifedipine completely inhibited pressure-induced AA vasoconstriction. In summary, pressure-induced AA vasoconstriction is insensitive to the action of ANP, is relatively refractory to cyclic GMP–mediated vasorelaxation, but is completely inhibited by calcium channel blockade. Furthermore, since ANP completely abolishes norepinephrine-induced vasoconstriction but fails to affect pressure-induced vasoconstriction, it is apparent that the type of underlying vasoconstrictor stimuli constitutes a major determinant of the renal microvascular response to ANP