scholarly journals Losartan Preserves Erectile Function by Suppression of Apoptosis and Fibrosis of Corpus Cavernosum and Corporal Veno-Occlusive Dysfunction in Diabetic Rats

2017 ◽  
Vol 42 (1) ◽  
pp. 333-345 ◽  
Author(s):  
Wen Ji Li ◽  
Mingxi Xu ◽  
Meng Gu ◽  
Da-chao Zheng ◽  
Jianhua Guo ◽  
...  

Background/Aims: Transforming growth factor-β1 (TGF-β1) plays important roles in penile corporal fibrosis and veno-occlusive dysfunction (CVOD). Angiotensin II (Ang II) is critically involved in erectile dysfunction, and blocking of Ang II is more important than inhibition of TGF-β in non-penile tissue fibrosis. However, the role of Ang II in corporal fbrosis and CVOD in a diabetic condition has not been investigated. Methods: Diabetic rats were treated with sildenafil or losartan (an Ang II antagonist) alone or in combination. Intracavernosal pressure, dynamic infusion cavernosometry, and histological and molecular alterations of the corpus cavernosum were examined. Results: Diabetic rats exhibited decreases in erectile response, severe CVOD, apoptosis, fibrosis, and activation of the TGF-β1 pathway. Treatment with sildenafil had a modest effect on erectile response and an insignificant suppressive effect on CVOD, apoptosis, fibrosis, and the TGF-β1 pathway. Although losartan greatly improved the histological and molecular changes and CVOD as compared with sildenafil, its effect on erectile response was low. The combination of sildenafil and losartan had superior effects on these parameters than did either compound alone. Conclusion: Ang II activation may be involved in apoptosis and fibrosis of the corpus cavernosum through Smad and non-Smad pathways, resulting in CVOD and ED. The low efficacy of sildenafil in a diabetic ED rat model was at least partly due to its inadequate effects on apoptosis, fibrosis, and CVOD.

2021 ◽  
Vol 10 (19) ◽  
pp. 4430
Author(s):  
Grażyna Sygitowicz ◽  
Agata Maciejak-Jastrzębska ◽  
Dariusz Sitkiewicz

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.


Cardiology ◽  
2015 ◽  
Vol 131 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Weili Qiao ◽  
Cheng Wang ◽  
Bing Chen ◽  
Fan Zhang ◽  
Yaowu Liu ◽  
...  

Objective: To investigate the effects of ibuprofen on cardiac fibrosis in a rat model of type 1 diabetes. Methods: The diabetic model was established by injecting streptozotocin into the rats. Then, ibuprofen or pioglitazone was given by gavage for 8 weeks. The cardiac fibrosis was assessed, and the major components of the renin-angiotensin system, the transforming growth factor β1 (TGF-β1) and the mammalian target of rapamycin (mTOR), were evaluated by histopathological, immunohistochemical, Western blot analysis or ELISA assay. Results: Obvious cardiac fibrosis was detected in the diabetic group and was alleviated by ibuprofen treatment. Angiotensin-converting enzyme (ACE), angiotensin (Ang) II and AngII type 1 receptor (AT1-R) levels were higher, and ACE2, Ang(1-7) and Mas receptor (Mas-R) were lower in the diabetic group. The ratio of ACE to ACE2 was raised in the diabetic group. All these changes were ameliorated by ibuprofen. TGF-β1 and mTOR were raised in the hearts of the diabetic group and were attenuated by ibuprofen treatment. There was no significant difference between the ibuprofen and the pioglitazone groups. Conclusion: Ibuprofen could ameliorate the cardiac fibrosis in diabetic rats by reduction of the ACE/AngII/AT1-R axis and enhancement of the ACE2/Ang(1-7)/Mas-R axis, leading to a decrease in TGF-β1 and mTOR.


2000 ◽  
Vol 278 (3) ◽  
pp. R640-R645 ◽  
Author(s):  
Kee Hwan Yoo ◽  
Barbara A. Thornhill ◽  
Robert L. Chevalier

Unilateral ureteral obstruction (UUO) induces activation of the renin-angiotensin system and upregulation of transforming growth factor-β1 (TGF-β1; a cytokine modulating cellular adhesion and fibrogenesis) and clusterin (a glycoprotein produced in response to cellular injury). This study was designed to examine the regulation of renal TGF-β1 and clusterin by ANG II in the neonatal rat. Animals were subjected to UUO in the first 2 days of life, and renal TGF-β1 and clusterin mRNA were measured 3 days later. Rats were divided into treatment groups receiving saline vehicle, ANG, losartan (AT1 receptor inhibitor), or PD-123319 (AT2 receptor inhibitor). ANG stimulated renal TGF-β1 expression via AT1 receptors, a response similar to that in the adult. In contrast, clusterin expression was stimulated via AT2 receptors, a response differing from that in the adult, in which ANG inhibits clusterin expression via AT1receptors. We speculate that the unique response of the neonatal hydronephrotic kidney to ANG II is due to the preponderance of AT2 receptors in the developing kidney.


2001 ◽  
Vol 281 (5) ◽  
pp. C1457-C1467 ◽  
Author(s):  
Gaétan Thibault ◽  
Marie-Josée Lacombe ◽  
Lynn M. Schnapp ◽  
Alexandre Lacasse ◽  
Fatiha Bouzeghrane ◽  
...  

Using a novel pharmacological tool with125I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: α8β1, α3β1, α5β1, αvβ1, and αvβ3. Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-β1 (TGF-β1) resulted in an increase of protein and heightening by 50% of the receptor density of α8β1-integrin. The effect of ANG II was blocked by an AT1, but not an AT2, receptor antagonist, or by an anti-TGF-β1 antibody. ANG II and TGF-β1 increased fibronectin secretion, smooth muscle α-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The α8- and β1-subunits were colocalized by immunocytochemistry with vinculin or β3-integrin at focal adhesion sites. These results indicate that α8β1-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-β1 in a myofibroblast-like phenotype suggests the involvement of α8β1-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.


2020 ◽  
Vol 48 (16) ◽  
pp. 8943-8958 ◽  
Author(s):  
Antonio Pezone ◽  
Maria Letizia Taddei ◽  
Alfonso Tramontano ◽  
Jacopo Dolcini ◽  
Francesca Ludovica Boffo ◽  
...  

Abstract The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT.


2020 ◽  
Vol 20 (11) ◽  
Author(s):  
Jiaxin Tong ◽  
Qingjia Gu

Abstract Purpose of Review This review highlights the expression and regulation of mucin in CRS and discusses its clinical implications. Recent Findings Chronic rhinosinusitis (CRS) is common chronic nasal disease; one of its main manifestations and important features is mucus overproduction. Mucin is the major component of mucus and plays a critical role in the pathophysiological changes in CRS. The phenotype of CRS affects the expression of various mucins, especially in nasal polyps (NP). Corticosteroids(CS), human neutrophil elastase (HNE), and transforming growth factor-β1 (TGF-β1) are closely related to the tissue remodeling of CRS and regulate mucin expression, mainly MUC1, MUC4, MUC5AC, and MUC5B. “It is expected that CS, HNE and TGF - β could be used to regulate the expression of mucin in CRS.” However, at present, the research on mucin is mainly focused on mucin 5AC and mucin 5B, which is bad for finding new therapeutic targets. Summary Investigating the expression and location of mucin in nasal mucosa and understanding the role of various inflammatory factors in mucin expression are helpful to figure out regulatory mechanisms of airway mucin hypersecretion. It is of great significance for the treatment of CRS.


2021 ◽  
Vol 100 (3) ◽  
pp. 88-96
Author(s):  
A.V. Eremeeva ◽  
◽  
V.V. Dlin ◽  
D.A. Kudlay ◽  
A.A. Korsunskiy ◽  
...  

Objective of the study: to study the clinical significance of the determination of angiotensin 2 (Ang II) and transforming growth factor β1 (TGF-β1) in urine of children with acute and chronic secondary pyelonephritis (PN) for increasing the efficiency of diagnosis of the disease. Materials and methods of research: a prospective open non-randomized controlled longitudinal single-center study was carried out in the Speransky City Children’s Hospital № 9 from January 10, 2015 to June 2020 to study the sensitivity and specificity of the tests under study. 60 children from 1 to 15 years old with acute and chronic secondary PN were examined. Children were divided into 2 groups: 1st – 30 patients with the onset of acute PN, 2nd – 30 patients with recurrent chronic secondary PN. The control group consisted of 20 apparently healthy children. In the 1st group of patients, girls predominated (24 children, 80%), the median age was 7 [3; 9] years, the median duration of followup is 41 [8; 45] months from the onset of the disease. In the 2nd group girls also predominated – 23 (77%), the median age – 8 [5; 11] years, the median duration of the disease at the time of inclusion in the study was 5 [3; 9] years. Most children were diagnosed with vesicoureteral reflux (VUR): grade I–II – in 18 (60%) and grade II–III – in 7 (23%). Incomplete renal doubling was detected in 4 (14%) patients, complete – in one (3%). The control group mainly consisted of girls – 16 (80%), the median age – 5,5 [3,25; 8,75] years. All patients underwent a study of general clinical and biochemical blood test, general analysis of urine, determination in a single morning portion of urine by enzyme immunoassay method according to ELISA TGF-β1 and Ang II. To standardize the level of TGF-β1 and Ang II in the urine, the level of creatinine in each portion of urine was determined and the results were converted to 1 mg of creatinine. Instrumental examination included ultrasound of the kidneys and bladder before and after micturition. Static nephroscintigraphy was performed 6 months after the onset of the disease or recurrence of chronic secondary PN. Results: it was found that at the onset of acute PN and with relapses of chronic secondary PN, there was an increased urinary excretion of TGF-β1 (p=0,002) and Ang II (p=0,002) when compared with the control group. It was shown that the level of increase in these markers depended on the form of PN. There were statistically significant differences in the urinary excretion of TGF-β1 and Ang II in children with acute PN and exacerbation of chronic secondary PN prior to the initiation of antibiotic therapy (p=0,001 and p=0,001, respectively). Urinary levels of Ang II and TGF-β1 in patients with exacerbation of chronic secondary PN in the first days of the microbial-inflammatory process in the renal parenchyma were by an order of magnitude higher than those in children with the onset of acute PN. A high degree of correlation was revealed between the level of uAng II/Cr and uTGF-β1/Cr (r=0,75, p=0,0001 and r=0,89, p=0,0001, respectively) in the 1st and 2nd groups of children (r=0,86, p=0,0001 and r=0,75, p=0,001, respectively) in the acute phase of the disease before antibiotic therapy with the data obtained during static nephroscintigraphy in the period of remission of the disease. Conclusion: the results indicate the importance of studying the urinary excretion of Ang II/Cr and TGF-β1/Cr as additional diagnostic markers for the identification of patients with a relapse current of PN, as well as to predict the degree of development of sclerotic processes in the renal tissue in children with different forms of PN.


2005 ◽  
Vol 11 (1) ◽  
pp. 33-39 ◽  
Author(s):  
Noboru Yoshimoto ◽  
Shinji Togo ◽  
Toru Kubota ◽  
Nobuyuki Kamimukai ◽  
Shuji Saito ◽  
...  

2005 ◽  
Vol 54 (9) ◽  
pp. 837-847 ◽  
Author(s):  
V. S. Thakur ◽  
B. Shankar ◽  
S. Chatterjee ◽  
S. Premachandran ◽  
K. B. Sainis

2008 ◽  
Vol 295 (5) ◽  
pp. E1234-E1242 ◽  
Author(s):  
Lin Tian ◽  
Cai Li ◽  
Jiping Qi ◽  
Peng Fu ◽  
Xiaoyan Yu ◽  
...  

Urotensin II (UII) was identified as the ligand for a novel G protein-coupled receptor, GPR14. UII was found not only to have a potent vasoconstrictive action but also to have profibrotic effects in the heart. The present study was to define whether UII and GPR14 also play important roles in diabetes-induced renal fibrosis and dysfunction. Diabetic rats were induced using streptozotocin, and the rat proximal tubular epithelial cells (NRK-52E) were used for the in vitro mechanism study. Results showed that expression of UII and GPR14 was significantly upregulated at both mRNA and protein levels in the diabetic kidneys compared with controls. The upregulated expressions of UII and GPR14 in the kidney were accompanied by significant increases in the renal profibrotic factor transforming growth factor (TGF)-β1 expression, the renal extracellular matrix (fibronectin and collagen IV) accumulation, and the renal dysfunction (increases in urinal N-acetyl-β-d-glucosaminidase content, 24-h urinary retinol-binding protein excretion rate, and decrease in creatinine clearance rate). Exposure of NRK-52E cells to 10−8 mol/l UII for 48 h caused a significant increase of TGF-β1, but not ANG II, production that was GPR14- and calcium-dependent, since GPR14 small-interfering RNA and calcium channel blocker nimodipine or calcium chelator EDTA all could abolish the induction of TGF- β1 by UII. Furthermore, exposure of NRK-52E cells to TGF-β1 or ANG II also increased UII and GPR14 mRNA expressions. These results suggested that diabetes-induced upregulation of UII and GPR14, most likely through autocrine and/or paracrine mechanisms, plays an important role in TGF-β1-mediated renal fibrosis and dysfunction.


Sign in / Sign up

Export Citation Format

Share Document