angiotensin-i and Ischemia

Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.

Topics: Angiotensin I; Animals; Humans; Ischemia; Kidney; Natriuretic Peptides; Neprilysin; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renal Insufficiency; Renin-Angiotensin System; Signal Transduction

Topics: Acute Kidney Injury; Angiotensin I; Animals; Antioxidants; Ischemia; Kidney; Male; MicroRNAs; NF-E2-Related Factor 2; Peptide Fragments; Rats; Reperfusion Injury

This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1-7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.

Topics: Acute Kidney Injury; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Diabetes Mellitus, Experimental; Diminazene; Imidazoles; Ischemia; Kidney; Liver; Male; Myocardium; Oxidative Stress; Peptide Fragments; Peroxidase; Rats, Wistar; Receptor, Angiotensin, Type 2; Sulfonamides; Thiophenes

The angiotensin (ANG)-(1-7)/Mas receptor (MasR) pathway activates vascular repair-relevant functions of bone marrow progenitor cells. We tested the effects of ANG-(1-7) on mobilization and vasoreparative functions of progenitor cells that are impaired in diabetes. The study was performed in streptozotocin-induced diabetic (db/db) mice. Diabetes resulted in a decreased number of Lineage

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angiotensin I; Animals; Blood Vessels; Bone Marrow; Bone Marrow Cells; Cell Lineage; Cell Movement; Chemokine CXCL12; Diabetes Mellitus, Experimental; Ischemia; Male; Membrane Proteins; Mice; Neovascularization, Physiologic; Peptide Fragments; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Recovery of Function; Regeneration; rho-Associated Kinases; Stem Cells; Vascular Endothelial Growth Factor A; Vasodilator Agents

The purpose of this study was to reveal the effect of angiotensin (1-7) on survival of random pattern, nicotinized, ischemic flap model in rats.. We used female Sprague Dawley rats weighing between 250 and 300 g. The study was performed on 3 groups each of them was consisted of 30 rats (control [C], angiotensin (1-7) [A] and vehicle [V]).While group C was subjected to 1 mL saline subcutaneous injection once daily for 28 days, groups A and V were nicotinized by 2 mg/kg nicotine subcutaneous injection, twice a day. At the end of this period, McFarlane random flap was constructed in all rats. No drug was applied to the flap bed in the group C, whereas for group A angiotensin (1-7) (A [1-7]) was delivered and a vehicle without an active ingredient was applied to the group V.Following surgery, immediately, Na-fluorescein diffusion tests were performed on 10 subjects of every group and necrotic areas were determined by millimetric paper method. After this, for determining angiogenesis, 10 subjects were killed from each group on the second day and fourth day. Finally, on the seventh day, necrotic areas were measured in 10 subjects of each group. They were then killed after photographs were taken. Specimens were collected from distal and critical zones of flaps, in all the groups, for immunohistochemical and histopathologic analyses.. Macroscopic measurements revealed equal ischemic areas for groups A and V in 30 minutes which were both larger than those of the group C (P < 0.005). Measurements performed on the seventh day showed a significant decrease of ischemia, which advanced to necrosis in the group A (P < 0.005). Groups V and C showed a direct progress to necrosis without changes in ischemia levels. Microscopic analysis exhibited a statistically significant increase in the number of microvascular structures and diameters of mature vascular structures in the group A compared with those of groups C and V (P < 0.005).. A (1-7) increased vasodilatation in nicotinized flaps, triggered angiogenesis in the first 2 days, and contributed remarkably to the flap survival.

Topics: Angiogenesis Inducing Agents; Angiotensin I; Animals; Female; Graft Survival; Ischemia; Necrosis; Neovascularization, Physiologic; Nicotine; Peptide Fragments; Rats; Rats, Sprague-Dawley; Skin Transplantation; Surgical Flaps; Vasodilation; Vasodilator Agents

We have investigated the effect of benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke and an agonist for the aryl hydrocarbon receptor (AHR), on hypoxia-induced angiogenesis. Ischemia was induced by femoral artery ligation in wild-type and AHR-null mice, and the animals were subjected to oral administration of B[a]P (125 mg/kg) once a week. Exposure to B[a]P up-regulated the expression of metallothionein in the ischemic hindlimb and markedly inhibited ischemia-induced angiogenesis in wild-type mice. The amounts of interleukin-6 and of vascular endothelial growth factor (VEGF) mRNA in the ischemic hindlimb of wild-type mice were reduced by exposure to B[a]P. These various effects of B[a]P were markedly attenuated in AHR-null mice. Our observations suggest that the loss of the inhibitory effect of B[a]P on ischemia-induced angiogenesis apparent in AHR-null mice may be attributable to maintenance of interleukin-6 expression and consequent promotion of angiogenesis through up-regulation of VEGF expression.

Topics: Angiotensin I; Animals; Aryl Hydrocarbon Receptor Nuclear Translocator; Benzo(a)pyrene; Carcinogens; Cytochrome P-450 CYP1A1; Femoral Artery; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Ischemia; Lower Extremity; Male; Metallothionein; Mice; Mice, Inbred Strains; Neovascularization, Physiologic; Receptors, Angiotensin; Receptors, Aryl Hydrocarbon; Receptors, Vascular Endothelial Growth Factor; Up-Regulation; Vascular Endothelial Growth Factor A

Cell-based therapy is a promising approach designed to enhance neovascularization and function of ischemic tissues. Interaction between endothelial and smooth muscle cells regulates vessels development and remodeling and is required for the formation of a mature and functional vascular network. Therefore, we assessed whether coadministration of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) can increase the efficiency of cell therapy. Unilateral hindlimb ischemia was surgically induced in athymic nude mice treated with or without intravenous injection of EPCs (0.5 x 10(6)), SMPCs (0.5 x 10(6)) and EPCs+SMPCs (0.25 x 10(6)+0.25 x 10(6)). Vessel density and foot perfusion were increased in mice treated with EPCs+SMPCs compared to animals receiving EPCs alone or SMPCs alone (P<0.001). In addition, capillary and arteriolar densities were enhanced in EPC+SMPC-treated mice compared to SMPC and EPC groups (P<0.01). We next examined the role of Ang-1/Tie2 signaling in the beneficial effect of EPC and SMPC coadministration. Small interfering RNA directed against Ang-1-producing SMPCs or Tie2-expressing EPCs blocked vascular network formation in Matrigel coculture assays, reduced the rate of incorporated EPCs within vascular structure, and abrogated the efficiency of cell therapy. Production of Ang-1 by SMPCs activates Tie2-expressing EPCs, resulting in increase of EPC survival and formation of a stable vascular network. Subsequently, the efficiency of EPC- and SMPC-based cotherapy is markedly increased. Therefore, coadministration of different types of vascular progenitor cells may constitute a novel therapeutic strategy for improving the treatment of ischemic diseases.

Topics: Angiotensin I; Animals; Endothelial Cells; Hindlimb; Humans; Ischemia; Male; Mice; Mice, Nude; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Receptor, TIE-2; Signal Transduction; Stem Cell Transplantation; Stem Cells

Topics: Angiotensin I; Animals; Endothelial Cells; Hindlimb; Humans; Ischemia; Male; Mice; Mice, Nude; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Receptor, TIE-2; Signal Transduction; Stem Cell Transplantation; Stem Cells

Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.

Topics: Angiography, Digital Subtraction; Angiotensin I; Angiotensin II; Arteriosclerosis; Captopril; Chymases; Female; Humans; Hyperaldosteronism; Hypertension, Renovascular; Ischemia; Kidney; Mast Cells; Middle Aged; Nephrectomy; Renal Artery; Renal Artery Obstruction; Renal Veins; Renin; Renin-Angiotensin System; Serine Endopeptidases; Smoking

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.

Topics: Angiotensin I; Angiotensin II; Animals; Chronic Disease; Chymases; Cilazapril; Dogs; Hemodynamics; Hypertension, Renal; Imidazoles; Ischemia; Kidney; Male; Oligopeptides; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Renal Circulation; Renin-Angiotensin System; Serine Endopeptidases; Tetrazoles

The pathophysiology of renal ischaemia, resulting in tubular cell injury and leading to acute renal failure (ARF), remains unclear. An ever-increasing number of investigations focus on a possible role of nitric oxide (NO) in regulating circulation during ARF. In this context, we investigated the influence of chronic stimulation or inhibition of NO synthesis, or both, on haemodynamic parameters, histology and plasma renin activity (PRA) after ischaemia-reperfusion injury of rat kidneys.. Experiments were performed on adult, male Wistar rats. Before induction of ARF, a group of animals was treated with a NO synthesis inhibitor (L-NAME) and another group was treated with a precursor of NO synthesis (L-arginine). The animals received those substances for 4 weeks. Control groups received the same amount of tap water for 4 or 8 weeks and were divided into groups with ARF (4 weeks--ARF group and 8 weeks ARF group) and a sham-operated group. Another group of rats was treated first with L-NAME and then with L-arginine in their drinking water, for 4 weeks for each of these two substances. All parameters were evaluated 24 h after the induction of ischaemic ARF or the sham operation.. Our results show that such long-term stimulation of NO release by L-arginine improved renal haemodynamics in the ischaemic form of ARF. Renal blood flow (RBF) increased by 96% in the L-arginine-treated rats with ARF compared with the group with ARF alone. Inhibition of NO synthesis worsens renal haemodynamics after ARF. However, this aggravation can be reversed by L-arginine. The rate of water reabsorption was reduced in all groups with ARF, but this reduction was least in the group treated with L-arginine. The rate of Na+ reabsorption was reduced in all groups 24 h after renal ischaemia, but a significant decrease was observed after the inhibition of NO synthesis. Histological examination of the kidney specimens showed that morphological changes were least in the rats treated with L-arginine, when compared with all other groups with ARF. Nevertheless, the lesions were most prominent in the L-NAME+ARF group. In this group, the areas of corticomedullar necrosis were more widespread in comparison with other groups, especially the L-arginine group where only swelling of the proximal tubular cells was observed. Treatment with L-NAME was not accompanied by any significant alteration in the plasma concentration of angiotensin I (ANG I), while in the group treated with L-arginine ANG I had a tendency to decrease.. Acute post-ischaemic renal failure may be alleviated by administering the NO substrate (L-arginine). NO acts cytoprotectively on tubular epithelial cells in ischaemia--reperfusion injury of rat kidney. Evidence of this comes from both histopathological findings and increased tubular water and sodium reabsorption. However, inhibition of NO synthesis (provoked by L-NAME) worsens renal haemodynamics and aggravates morphological changes after ARF. These aggravations can, however, be reversed by L-arginine.

Topics: Acute Kidney Injury; Angiotensin I; Animals; Arginine; Ischemia; Kidney; Kidney Tubules; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar

The brain oedema, distribution space (DS) and brain uptake index (BUI), of L-glucose, inulin, B12 vitamin and of three polypeptidic hormones of increasing molecular weight (angiotensin-I, gastrin and insulin) were measured in the rat after sham operation, porto-caval shunt (PCS) or liver ischaemia. At an early stage following PCS or liver ischaemia brain oedema was not constant, and was only demonstrable after liver ischaemia in a large number of animals. Substances without an active transport and with a low diffusion coefficient such as L-glucose and inulin had a very low BUI, unchanged even if the 3H2O brain content or the DS were modified. B12 vitamin, DS and BUI were very high and did not change after liver ischaemia or PCS. Insulin DS and BUI were low in the three groups of animals, whereas it decreased after PCS for gastrin. A significant increase of BUI and DS (without any cerebral oedema) was demonstrated for angiotensin-I, a polypeptidic hormone of molecular weight 1300. This polypeptidic marker is in the same range of MW as the preliminary recently recognized medium-sized molecules which may be involved in the pathogenesis of encephalopathy during experimental acute liver failure. However, not only the MW, but the nature of such polypeptides may be of importance in the genesis of this limited impairment of BBB permeability.

Topics: Acute Disease; Angiotensin I; Animals; Blood-Brain Barrier; Brain Edema; Ischemia; Liver; Male; Molecular Weight; Permeability; Portacaval Shunt, Surgical; Rats; Rats, Inbred Strains; Vitamin B 12