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

Experimentelle Schlaganfallbehandlung mittels CD34+- und CD34--Nabelschnurblutzellen in spontan hypertensiven Ratten

Human umbilical cord blood as a source of stem cells has recently been reported in experimental treatment of cerebral disorders. However, little is known about the nature of cells and cellular mechanisms leading to neurofunctional improvement. Here we investigated the potential of separated CD34+ versus CD34- human umbilical cord blood cells (HUCBC) to promote functional recovery following stroke. The experiments were performed in spontaneously hypertensive (SH) rats, known for a risk profile comparable to stroke patients.After three weeks of behavioral training in the RotaRod and Beamwalk test arrays, stroke was induced by permanent middle cerebral artery occlusion (MCAO). For cell therapy, 1x106 cryopreserved cells were administered systemically between 8 and 10 hours after MCAO. The behavioral tests were performed together with a neurological severity score (mNSS) until day 29 to assess neurofunctional disabilities. Nearly complete functional remission was observed with both subpopulations CD34+ as well as CD34- cells. To localize cells histologically, they were labeled with a fluorescence dye (CFSE) before injection. Again, after administration of CD34+ as well as CD34- cells, CFSE labelled cells were found that accumulated in the border zone between the central necrosis of the ischemic lesion and functional brain tissue, thus indicating active attraction towards the lesion for both cell populations. Immunohistology with anti-CD68 and antibodies to human neuronal markers (NF-L, chromogranin) indicated an accumulation of human and rat monocytes in the border zone of the lesion while neuronal cells of human origin could not be detected in host brains.Obwohl humanes Nabelschnurblut als Quelle von Stammzellen für experimentelle Therapien von Erkrankungen des Zentralnervensystems derzeit intensiv untersucht wird, ist noch wenig über die zellulären Prozesse bekannt, die der funktionellen Verbesserung von Ausfallerscheinungen zugrunde liegen. In der vorliegenden Studie untersuchten wir das Potenzial humaner Nabelschnurblutzellen, funktionelle Verbesserungen nach einem experimentellen Schlaganfall zu unterstützen. Die Experimente wurden mit spontan hypertensiven (SH) Ratten durchgeführt, deren metabolische Grunderkrankungen dem Risikoprofil menschlicher Schlaganfallpatienten entsprechen.Nach drei Wochen der Konditionierung für die Verhaltenstests RotaRod und Beamwalk wurde ein experimenteller Schlaganfall durch permanente Okklusion der mittleren Hirnarterie (middle cerebral artery occlusion, MCAO) ausgelöst. Im Zuge der Zelltherapie wurden 1x106 kryokonservierte CD34+- oder CD34--Zellen 8 bis 10 Stunden nach Verschluss der rechten mittleren Hirnarterie intravenös appliziert. Die Verhaltenstests wurden zusammen mit der Erhebung des modified neurological severity score (mNSS) bis 29 Tage nach Eintritt des experimentellen Schlaganfalls durchgeführt, um die Entwicklung neurofunktionaler Defizite im Verlauf beurteilen und quantifizieren zu können. Dabei wurde eine annähernd komplette Rückbildung von Ausfallerscheinungen bei Gabe beider Zellpopulationen beobachtet. Um transplantierte Zellen lokalisieren zu können, wurden diese mit dem Fluoreszenzfarbstoff CFSE unmittelbar vor der systemischen Zellgabe markiert. Sowohl nach der Gabe von CD34+- als auch CD34--Zellen konnten CFSE-markierte Zellen in der Grenzzone zwischen zentraler Kolliquationsnekrose und funktionellem Hirngewebe detektiert werden. Immunhistologische Untersuchungen mit anti-CD68 Antikörpern gegen neuronale Marker (NF-L, Chromogranin) zeigten eine verstärkte Ansammlung von Zellen monozytärer Natur, während neuronale Zellen humanen Ursprungs nicht identifiziert werden konnten

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

Monitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat

In vivo monitoring of stem cells after grafting is essential for a better understanding of their migrational dynamics and differentiation processes and of their regeneration potential. Migration of endogenous or grafted stem cells and neurons has been described in vertebrate brain, both under normal conditions from the subventricular zone along the rostral migratory stream and under pathophysiological conditions, such as degeneration or focal cerebral ischemia. Those studies, however, relied on invasive analysis of brain sections in combination with appropriate staining techniques. Here, we demonstrate the observation of cell migration under in vivo conditions, allowing the monitoring of the cell dynamics within individual animals, and for a prolonged time. Embryonic stem (ES) cells, constitutively expressing the GFP, were labeled by a lipofection procedure with a MRI contrast agent and implanted into rat brains. Focal cerebral ischemia had been induced 2 weeks before implantation of ES cells into the healthy, contralateral hemisphere. MRI at 78-μm isotropic spatial resolution permitted the observation of the implanted cells with high contrast against the host tissue, and was confirmed by GFP registration. During 3 weeks, cells migrated along the corpus callosum to the ventricular walls, and massively populated the borderzone of the damaged brain tissue on the hemisphere opposite to the implantation sites. Our results indicate that ES cells have high migrational dynamics, targeted to the cerebral lesion area. The imaging approach is ideally suited for the noninvasive observation of cell migration, engraftment, and morphological differentiation at high spatial and temporal resolution