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Indirect immunofluorescence to evaluate Ang II expression in adriamycin-induced nephrotic syndrome (NS). Renal sections were stained using an anti-Ang II antibody and a secondary TRIC-conjugated antibody. (A) Ang II-positive cells in a glomerulus (arrows) and interstitium (crossed arrows). (B) Tubular expression of Ang II (asterisks) and interstitial positive cells (crossed arrows) in a damaged tubulointerstitial section. Note a negative and broken tubule (arrow). (C) Interstitial (crossed arrows) and tubular (arrow) Ang II accumules. Asterisk shows an Ang II-negative tubule with intense tubular dilation. Original magnification: ×400.
Source publication
Nephrotic syndrome induced by adriamycin (ADR) is an experimental model of glomerulosclerosis in humans. The AT(1) receptor for angiotensin II (Ang II) is involved in the renal expression of the nuclear factor-kappa B (NF-ΚB) during this nephrosis. NF-ΚB is a transcription factor for proinflammatory effects of Ang II; however, there is no informati...
Citations
... Our research has shown that the levels of proinflammatory factors can be quantified in LV tissue. Ang-II is recognized for its ability to boost the production of specific inflammatory cytokines through its binding to the AT1R [24]. One such cytokine is TNF-α, a critical component of the innate immune system. ...
Background:
The use of Adriamycin (ADR), also known as doxorubicin, as a chemotherapy agent is limited by its detrimental adverse effects, especially cardiotoxicity. Recent studies have emphasized the crucial role of angiotensin II (Ang-II) in the development of ADR-induced cardiomyopathy. This study aimed to explore the potential cardioprotective effects of losartan in a rat model of ADR-induced cardiomyopathy.
Methods:
Male Sprague-Dawley rats were randomly divided into 3 groups: a control group (group C), an ADR-treated group (ADR 5 mg/kg/wk for 3 weeks via intraperitoneal injections; group A), and co-treatment of ADR with losartan group (same dose of ADR and losartan; 10 mg/kg/day per oral for 3 weeks; group L). Western blot analysis was conducted to demonstrate changes in brain natriuretic peptide, collagen 1, tumor necrosis factor (TNF)-α, interleukin-6, matrix metalloproteinase (MMP)-2, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), and caspase-3 protein expression levels in left ventricular (LV) tissues from each group.
Results:
Losartan administration reduced LV hypertrophy, collagen content, and the expression of pro-inflammatory factors TNF-α and MMP-2 in LV tissue. In addition, losartan led to a decrease in the expression of the pro-apoptotic proteins Bax and caspase-3 and an increase in the expression of the anti-apoptotic protein Bcl-2. Moreover, losartan treatment induced a reduction in the apoptotic area compared to group A.
Conclusion:
In an ADR-induced cardiomyopathy rat model, co-administration of ADR with losartan presented cardioprotective effects by attenuating LV hypertrophy, pro-inflammatory factors, and apoptosis in LV tissue.
... Since dengue is an inflammatory disease, it is justified to study the effect of anti-Ang II drugs on this disease. In this regard, anti-Ang II drugs in several experimental models of inflammatory diseases have been reported [267][268][269]. More research is needed to determine whether there is a direct association between DENV and Ang II production in in vitro and in vivo models and to establish whether increased expression of this hormone occurs in patients infected with DENV. ...
Dengue is a disease caused by a flavivirus that is transmitted principally by the bite of an Aedes aegypti mosquito and represents a major public-health problem. Many studies have been carried out to identify soluble factors that are involved in the pathogenesis of this infection. Cytokines, soluble factors, and oxidative stress have been reported to be involved in the development of severe disease. Angiotensin II (Ang II) is a hormone with the ability to induce the production of cytokines and soluble factors related to the inflammatory processes and coagulation disorders observed in dengue. However, a direct involvement of Ang II in this disease has not been demonstrated. This review primarily summarizes the pathophysiology of dengue, the role of Ang II in various diseases, and reports that are highly suggestive of the involvement of this hormone in dengue.
... AT1R is the main receptor for AngⅡ in the kidney (Chi-Xianggeng et al., 2015). Nevertheless, AngⅡ is only biologically active when it recognizes and binds to its specific receptor (Muñoz et al., 2011). Although our results demonstrate the effect of losartan on AngII-TRPC6, as an Ang II receptor antagonist, losartan can improve hemorheology, renal hemodynamics, reduce renal vascular resistance, and reduce glomerular pressure, which may have a therapeutic effect on proteinuria. ...
Background: Nephrotic syndrome (NS) is a common glomerular disease, and podocyte injury is the character of primary NS, usually caused by minimal change disease and membranous nephropathy. Podocytopathy is primarily associated with glomerular proteinuria. Losartan, an angiotensin receptor blocker (ARB), is commonly used in the treatment of NS, and the AngiotensinⅡ (AngⅡ)–transient receptor potential ion channel 6 (TRPC6) axis has been reported to act on podocytes to regulate proteinuria in NS. Therefore, the purpose of this study was to explore the relationship in between AngⅡ–TRPC6, podocyte injury, and proteinuria based on the adriamycin (ADR) NS rat model.
Method: All male rats were divided into three groups: control group, model group, and ARB group. The rats in the model group were induced by ADR, and the rats in the ARB group received losartan after induction of renal injury for 4 weeks. The changes in parameters related to renal dysfunction, and glomerular and podocyte structural damage, such as AngⅡ, AngⅡ type I receptor (AT1R), TRPC6, CaN, Caspase-3, Nephrin, and Podocin, were analyzed. Furthermore, the kidneys were isolated for study via transmission electron microscopy (TEM), immunohistochemistry, and western blot (WB) after the rats were sacrificed. In vitro, immortalized mouse MPC5 podocytes were used to investigate the regulatory effect of flufenamic acid (Flu) and SAR7334 (SAR) on the AngⅡ-TRPC6 signaling axis. Flow cytometry and WB were conducted to determine the relationship between podocyte injury and AngⅡ-TRPC6.
Results: In vivo results showed that NS rats developed massive albuminuria and abnormal renal function, accompanied by abnormally increased levels of AngⅡ, TRPC6, AT1R, and CaN and a decreased expression of actin molecules in podocytes, extensive fusion of foot processes (FP), loss of glomerular structural integrity, collapse of podocyte structure, and skeletal reorganization. In vitro experiments indicated that both AngⅡ and Flu (the specific agonist of TRPC6) stimulated the expressions of TRPC6, AT1R, and Caspase-3 in podocytes. The AngⅡ receptor–blocker losartan and TRPC6-specific inhibitor SAR blocked the overexpression of the aforementioned proteins. In addition, SAR also attenuated the degradation of podocyte structural proteins and inhibited the fluorescence intensity of intracellular calcium (Ca²⁺) and cell apoptosis.
Conclusion: The involvement of AngⅡ in the occurrence of NS proteinuria may be related to podocyte injury induced by activated TRPC6.
... Grupo ETZ + Vehículo: recibió vía oral 500 ul de agua destilada. (Muñoz, et al., 2011) El losartán es un antagonista de los receptores AT1 de la Angiotensina II (Smith, 2008); mientras que el enalapril es un inhibidor de la enzima convertidora de angiotensina I (Vargas et al. 2012). ...
... La angiotensina II es el principal efector biológico del SRA y se ha reconocido desde hace muchos años como un agente vasoconstrictor tanto local como sistémico, cuyas acciones pueden modificar la reabsorción de agua y electrolitos a nivel del túbulo contorneado distal (Miller y Arnold 2019). Además la angiotensina II posee propiedades proinflamatorias las cuales puede ejercer sobre diferentes tejidos, incluyendo el tejido cardíaco y vascular (Muñoz et al. 2011;Wang et al. 2016;Miller y Arnold 2019). Esta acción es mediada a través de su unión a receptores AT1 principalmente (Miller y Arnold 2019;Zhou et al. 2007). ...
The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.
... La Ang II es el principal efector biológico del SRA y se ha reconocido desde hace muchos años como un agente vasoconstrictor tanto local como sistémico, cuyas acciones pueden modificar la reabsorción de agua y sodio en los segmentos tubulares distales de la nefrona (no directamente, sino a través de la aldosterona). Además la angiotensina II es una potente molécula proinflamatoria que puede actuar sobre diferentes tejidos, incluyendo el tejido cardíaco (Muñoz et al. 2011;Wang et al. 2016;Miller y Arnold 2019). Esta acción de la angiotensina II sobre diversos tejidos es mediada a través de su unión a receptores AT1 y AT2 (Miller y Arnold 2019;Zhou et al. 2007). ...
... Grupo ETZ + Enalapril: recibió vía oral 18 mg/kg/día de enalapril. (Merck Sharp & Dohme, Chalfont, Pennsylvania, United States)(Muñoz et al. 2011). ...
... De acuerdo a este mecanismo, nuestros resultados sugieren que el losartán es capaz de bloquear el receptor AT1, de tal manera que se bloquee el efecto de la angiotensina II, lo que se traduce en una disminución en la expresión de RAGE(Muñoz et al. 2011;Goldin et al. 2006). Además se ha reportado que la hiperglicemia fue capaz de activar el sistema renina angiotensina en un modelo de diabetes mellitus inducido por ETZ). ...
El receptor para productos finales de glicación avanzada (RAGE) puede interactuar con diversos ligandos e inducir procesos inflamatorios. El objetivo de esta investigación fue determinar el efecto del enalapril y losartán sobre la expresión de RAGE en el tejido cardíaco en un modelo experimental de diabetes. Se utilizaron ratas Sprague-Dawley machos, con un peso de 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control, diabéticas, diabéticas tratadas con losartán y diabéticas tratadas con enalapril. La expresión de RAGE en miocardio se determinó por inmunofluorescencia indirecta. Se observó un aumento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.01), hubo una disminución en la expresión de RAGE miocárdico, sólo en los animales tratados con losartán versus los diabéticos sin tratamiento (p<0.05). En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión miocárdica de RAGE, la cual puede revertirse mediante el tratamiento con losartán lo cual indica la participación del sistema renina angiotensina en los mecanismos relacionados con el daño cardiaco durante la diabetes.
... The adriamycin-induced CKD model is known to exhibit prominent inflammation and podocyte damage, leading to glomerulosclerosis and tubulointerstitial fibrosis (Lee and Harris, 2011;Szalay et al., 2015) against which renin-angiotensin-aldosterone system blocking agents, ACE inhibitors and ARBs such as losartan, showed a small or limited renoprotective effect (Nakhoul et al., 2005;Muñoz et al., 2011). Our results also showed losartan had a small or limited effect on renal dysfunction at 30 mg/kg. ...
Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 (7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine) in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENT: The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain (NOD)-RIP2 axis might play a crucial role in pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.
... Animals with diabetes were divided into the following 3 groups (n¼6 each) at week 4 (glycemia: 380.3AE84.2 mg/dL) after STZ injection: an STZ-losartan group ( (11); and an STZ-vehicle group, which was given distilled water. Losartan is an antagonist of Ang II receptor type 1 (AT-1) (16) and enalapril is an inhibitor of angiotensin I-converting enzyme (17), and both were diluted in distilled water (500 mL). ...
... According to this mechanism, our results suggest that losartan is capable of blocking AT-1 receptor, inducing a decreased effect on myocardial leukocyte infiltration induced by RAGE. This anti-inflammatory effect after AT-1 blocking has been reported in several experimental models (10,11,23). In addition, hyperglycemia activated the RAS in the STZ-induced diabetes mellitus model (24), and increased expression of Ang II in brain vessels has been reported in this model (10), suggesting a common pathway of Ang II and RAGE in this model. ...
... In this regard, ET-1, the renin-angiotensin-aldosterone system and RAGE activation have been implicated in the human myocardium in diabetes (38). As expected, blocking of AT-1 receptor or inhibition of Ang II production led to decreased vasoconstrictor and proinflammatory effects of Ang II (10,11,15). ...
Objective
It is known that the receptor for advanced glycation end products (RAGE) activation is involved in the pathogenesis of cardiovascular disease in diabetes. Previous studies have shown the presence of angiotensin II (Ang II) in diabetes, suggesting a role for this hormone during the disease. However, the association of RAGE with Ang II during pathological cardiac remodeling follow STZ (streptozotocin)-induced diabetes remains unclear. Since Ang II is capable of inducing pro-inflammatory events, blocking its production (enalapril) and its action on its receptor (losartan) could decrease inflammatory events in the myocardium during this experimental model of diabetes. Therefore, the aim of this study was to determine the association of RAGE expression/inflammatory events/Ang II in the myocardium during STZ diabetes.
Method
Diabetes was induced by intravenous injection of STZ in Sprague-Dawley rats. Myocardial expressions of RAGE, monocyte/macrophage (ED-1 positive cells) infiltration and the intercellular adhesion molecule-1 (ICAM-1) were determined by histochemical methods. Levels of circulating endothelin-1 (ET-1) were determined by ELISA. The effects of Ang II were blocking by using losartan (15 mg/kg bw, daily by gastric gavage) or enalapril (18 mg/kg bw, daily by gastric gavage).
Results
This study showed increased expressions of RAGE and ED-1 in the myocardium; however, myocardial vascular ICAM-1 expression remained unchanged. Circulating levels of ET-1 in STZ rats were found increased. Renin-angiotensin system inhibition decreased the expressions of myocardial RAGE, ED-1 and ET-1 levels.
Conclusions
This study suggests a role of Ang II on myocardial inflammation in STZ-induced diabetes mediated by RAGE and ET-1.
... AT1 receptors are located at the nerve terminals. Losartan is also able to attenuate activation of the intrarenal renin-angiotensin system by inhibiting renal sympathetic outflow (53) . ...
... Angiotensin II is considered a growth factor that regulates events such as apoptosis, cell proliferation, renal fibrosis, and renal recruitment of inflammatory cells [7]. In severe renal tissue deterioration and dysfunction, such as in ureteral obstructions, losartan, angiotensin II type 1 (AT1) receptor antagonists, may reverse renal tissue damage [8]. ...
... It has also been reported that inhibition of the reninangiotensin system may improve renal function in cisplatin-injected rats [14,47]. Other investigators [7] reported that AT1 receptor antagonists and angiotensinconverting enzyme inhibitors had been used to reduce renal injury. They added that, in experimental models of chronic renal diseases, antagonists of AT1 receptor had shown renoprotective effects. ...
... With the advent of drugs such as Losartan that specifically blocks the Ang II AT-1 receptor and Enalapril that blocks ACE activity, it is possible to dissect the physiological roles of the renin-angiotensin system (Abdi & Johns 1997;Donmez et al. 2002;Benigni et al. 2010;Muñoz et al. 2011;Peña et al., 2013). Therefore, the aim of this study was to determine the role of Ang II in the renal oxidative stress and CD8 cell infiltration in rats treated with HgCl 2 using the angiotensin II receptor (AT-1) blocker Losartan and the ACE inhibitor Enalapril. ...
... Rats with no HgCl 2 treatment (Groups IV, V and VI) received, respectively, Enalapril, Losartan or normal saline only daily by gavage (500 ml). The Anti-Ang II doses used here were previously shown to be capable of diminishing pro-inflammatory events in different inflammatory models (Vargas et al. 2012;Muñoz et al. 2011;Peña et al. 2012). ...
... Therefore, when the anti-Ang II treatment is given 3 days after HgCl 2 injection, it may be acting after the initiation of renal cellular injury. Muñoz et al. (2011) showed that use of this anti-Ang II pre-treatment (3 days before and then throughout the experimental period) protocol diminished the expression of Ang II and pro-inflammatory molecules in an Adriamycininduced nephrosis model. The specific dose of HgCl 2 (2.5 mg/kg) and evolution time (96 h) used here were selected based on the fact that: (1) doses ranging from 1.0-3.5 mg HgCl 2 /kg induce dose-dependent alterations in the cytoplasm and nucleus of proximal tubular cells in rats (Stacchiotti et al. 2003); and (2) important inflammatory events are seen 2-6 days post-exposure (Ghielli et al. 2000). ...
Mercuric chloride (HgCl2) induces kidney damage, in part, through oxidative stress. A role for angiotensin II (Ang II) in pro-inflammatory events in a model of acute HgCl2-induced nephropathy was reported. Ang II is a potent oxidative stress inducer; however, its role in oxidative/anti-oxidative events in HgCl2-induced nephropathy remains unknown. The aim of this study was to determine the role of Ang II in the oxidative stress and renal infiltration of CD8(+) T-cells after an acute HgCl2 intoxication. Three groups of Sprague Dawley rats were treated with a single subcutaneous dose of 2.5 mg/kg HgCl2: for 3 days prior to and for 4 days after that injection, rats in one group received Losartan (30 mg/kg), in another group Enalapril (30 mg/kg) or normal saline in the last group. Two other groups of drug-treated rats received saline in place of HgCl2. A final group of rats received saline in place of HgCl2 and the test drugs. All treatments were via gastric gavage. At 96 h after the vehicle/HgCl2 injection, blood and kidney samples were harvested. Renal sections were homogenized for measures of malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity. Frozen sections were studied for the presence of superoxide anion ([Formula: see text]) and CD8(+) T-cells. HgCl2-treated rats had increased interstitial and tubular expression of [Formula: see text], high levels of MDA, normal catalase activity and GSH content, increased levels of interstitial CD8(+) T-cells and an increased percentage of necrotic tubules. Anti-Ang II treatments diminished the HgCl2-induced increases in interstitial [Formula: see text], CD8(+) T-cells and tubular damage and increased catalase and GSH expression above that due to HgCl2 alone; the HgCl2-induced high MDA levels were unaffected by the drugs. These data provide new information regarding the potential role of Ang II in the oxidative stress and renal CD8(+) T-cell infiltration that occur during HgCl2 nephropathy.
