Background. Based on previous data, we hypothesized that an increase of angiotensin II (Ang II)—via the Ang II type 1 (AT-1) receptor—in the rostral ve

Background. Oxidative stress is a state in which excess reactive oxygen species (ROS) overwhelm endogenous antioxidant systems. It is known that this s

The aim of the present study was to examine the participation of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats submitted to the renovascular Goldblatt (two-kidney, one clip) procedure. We inhibited or stimulated this area with the use of drugs such as glycine, l -glutamate, or kynurenic acid. (1) Bilateral microinjection of glycine (100 nmol, 200 nL, n=13) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 177.2±29.3 to 102.3±20.9 mm Hg ( P <.05), which was similar to the decrease produced by intravenous administration of hexamethonium. The inhibition of RVLM with glycine in normotensive rats produced a decrease in MAP from 106±17.1 to 59.7±7.3 mm Hg ( P <.05, n=9). (2) An impressive increase in MAP from 153.3±16.3 to 228±34.9 mm Hg ( P <.05) occurred in hypertensive rats after microinjection of l -glutamate (50 nmol, 200 nL, n=6) into the RVLM. The same procedure caused a significant but less intense increase in MAP from 105±13.8 to 148.3±24.9 mm Hg in normotensive rats ( P <.05, n=6). (3) A decrease in MAP from 151.6±25.3 to 96.8±22.5 mm Hg occurred in hypertensive rats after microinjection of the broad-spectrum glutamate antagonist kynurenic acid (4 nmol, 200 nL, n=6) into the RVLM, whereas the same procedure did not change MAP in normotensive animals (n=6). Heart rate was not significantly affected in any group. Together these results show that the activity of RVLM neurons is important in the maintenance of arterial blood pressure in Goldblatt hypertensive rats and probably indicate a change in the sensitivity and/or number of glutamatergic receptors in this area after the development of hypertension.

Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×10⁵ cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT₁ were elevated, whereas AT₂ levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.

Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α₁-adrenoreceptor tubular activation, a process independent of changes in systemic blood pressure, renal blood flow, or glomerular filtration rate. However, the underlying mechanism of the reabsorption of sodium is not fully understood. Since the sympathetic nervous system and intrarenal ANG II appear to act synergistically to mediate the process of sodium reabsorption, we hypothesized that low-frequency acute electrical stimulation of the renal nerve (ESRN) activates NHE3-mediated sodium reabsorption via ANG II AT₁receptor activation in Wistar rats. We found that ESRN significantly increased urinary angiotensinogen excretion and renal cortical ANG II content, but not the circulating angiotensinogen levels, and also decreased urinary flow and pH and sodium excretion via mechanisms independent of alterations in creatinine clearance. Urinary cAMP excretion was reduced, as was renal cortical PKA activity. ESRN significantly increased NHE3 activity and abundance in the apical microvillar domain of the proximal tubule, decreased the ratio of phosphorylated NHE3 at serine 552/total NHE3, but did not alter total cortical NHE3 abundance. All responses mediated by ESRN were completely abolished by a losartan-mediated AT₁receptor blockade. Taken together, our results demonstrate that higher NHE3-mediated proximal tubular sodium reabsorption induced by ESRN occurs via intrarenal renin angiotensin system activation and triggering of the AT₁receptor/inhibitory G-protein signaling pathway, which leads to inhibition of cAMP formation and reduction of PKA activity.