NLRP3 Deletion Attenuated Angiotensin II-Induced Renal Fibrosis by Improving Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Nephron ◽  
2021 ◽  
pp. 1-10
Author(s):  
Yumei Zhang ◽  
Yuqing Liu ◽  
Xiao Bi ◽  
Chun Hu ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Renal Fibrosis ◽  
Mitochondrial Morphology ◽  
Ang Ii ◽  
Wild Type ◽  
Caspase 12

<b><i>Background:</i></b> Increasing evidence suggests that angiotensin II (Ang II), the bioactive pro-oxidant in the renin-angiotensin system, aggravates fibrosis, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in multiple diseases, such as renal fibrosis. However, the role and underlying mechanism of Ang II in renal fibrosis remain unclear. Here, we investigated whether the NLRP3 inflammasome mediated Ang II-induced renal fibrosis, as well as the downstream pathways involved in this process. <b><i>Methods:</i></b> NLRP3<sup>−/−</sup> mice were used as a model to study Ang II-infused renal fibrosis. Mice were divided into 4 groups: sham wild type, Ang II-infused wild type, sham NLRP3<sup>−/−</sup>, and Ang II-infused NLRP3<sup>−/−</sup> groups. Ang II infusion-induced renal injury was confirmed by periodic acid-Schiff and Masson’s staining, immunohistochemistry, and transmission electron microscopy (TEM). Mitochondrial morphology was presented on TEM micrographs, and mitochondrial function was reflected by the protein levels of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), dynamin-related protein 1 (DRP1), and mitofusin 2 (MFN2), as assessed by Western blotting. Endoplasmic reticulum (ER) stress was characterized by changes in the levels of ER chaperones, such as GRP94, BiP, CHOP, and caspase 12. <b><i>Results:</i></b> Ang II infusion increased cell proliferation, extracellular matrix overproduction, inflammatory cell infiltration, and glomerulosclerosis and induced obvious morphological abnormalities in podocytes. Ang II infusion promoted mitochondrial damage, as indicated by TEM, and induced mitochondrial dysfunction, as evidenced by downregulation of PGC-1α, TFAM, and increased mitochondrial ROS. In addition, DRP1 expression was upregulated, while MFN2 expression was markedly decreased. The levels of GRP94, BiP, CHOP, and caspase 12 were significantly increased. However, all these detrimental effects were attenuated by NLRP3 deletion. <b><i>Conclusions:</i></b> NLRP3 deletion may attenuate angiotensin II-induced renal fibrosis by improving mitochondrial dysfunction and ER stress.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

Abstract 1494: Hepatocyte Growth Factor Attenuates Angiotensin II Induced Renal Fibrosis through TGF-β1 Suppression by Anoikis of Myofibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kazuma Iekushi ◽  
Yoshiaki Taniyama ◽  
Junya Azuma ◽  
Fumihiro Sanada ◽  
Norio Dosaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Renal Fibrosis ◽  
Type I ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Apoptosis ◽  
Hepatocyte Growth ◽  
Tgf Β1

Progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA positive myofibroblast which produce high amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Previous studies demonstrated that hepatocyte growth factor (HGF) improved kidney fibrosis in murine models, where direct molecular mechanisms of myofibroblasts have not yet been understood. We tested the hypothesis in vivo using cardiac specific overexpression HGF mice (HGF-Tg), which showed a significant increase in serum HGF concentration. Angiotensin II (Ang II) infusion significantly induced renal fibrosis in wild type mice, while renal fibrosis was significantly decreased in HGF-Tg mice accompanied by the degrease in interstitial myofibroblasts (P<0.05). Quantitative analysis demonstrated 1.69-folds induction of profibrtic cytokine, TGF-β1 mRNA in HGF-Tg with Ang II group compared with wild type with Ang II, and Collagen type I and IV mRNA expression was significantly decreased in HGF-Tg mice with Ang II. The antifibotic action of HGF-Tg mice was concordant with an increase in MMP-2, MMP-9 expression (1.32-fold, 1.33-fold vs wild type with Ang II infusion, P<0.05, respectively), and decreased TIMP-1, TIMP-2 expression (1.5-fold, 1.28-fold vs wild type with Ang II infusion, P<0.05, respectively). To further investigate the anti-fibrotic effect of HGF, we used cultured human mesangial cells (HMC). When HMC were treated with TGF-β1, cells underwent to phenotypic change similar to myofibroblasts, accompanied by the significant increase in c-Met/HGF receptor (P<0.05). Under such conditions, HGF induced anoikis-induced apoptosis of myofibroblasts. It also linked with FAK phosphorylation especially p-FAK (Y925) (P<0.05). When GM6001 (a broad-spectrum MMP inhibitor) was added with HGF, HGF-induced apptosis was significantly decreased. It was suggested that increased activities of MMPs underlie the major mechanism of HGF mediated anoikis induced apoptosis. The present study demonstrated that HGF elicited myofibroblast anoikis. Activation of MMPs in fibrotic kidney might be considered as a target to attenuate the progression of CKD.

scholarly journals Role of microRNA 690 in Mediating Angiotensin II Effects on Inflammation and Endoplasmic Reticulum Stress

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1327
Author(s):  
Kalhara R. Menikdiwela ◽  
Latha Ramalingam ◽  
Mostafa M. Abbas ◽  
Halima Bensmail ◽  
Shane Scoggin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Ang Ii ◽  
Protective Function

Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.

scholarly journals Mitoquinone Protects Podocytes from Angiotensin II-Induced Mitochondrial Dysfunction and Injury via the Keap1-Nrf2 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Zijing Zhu ◽  
Wei Liang ◽  
Zhaowei Chen ◽  
Jijia Hu ◽  
Jun Feng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Fission ◽  
Mitochondrial Morphology ◽  
Related Factor ◽  
Ang Ii ◽  
Mitochondrial Injury ◽  
Nrf2 Signaling Pathway

Podocyte mitochondrial dysfunction plays a critical role in the pathogenesis of chronic kidney disease (CKD). Previous studies demonstrated that excessive mitochondrial fission could lead to the overproduction of reactive oxygen species (ROS) and promote podocyte apoptosis. Therefore, the maintenance of stable mitochondrial function is a newly identified way to protect podocytes and prevent the progression of CKD. As a mitochondria-targeted antioxidant, mitoquinone (MitoQ) has been proven to be a promising agent for the prevention of mitochondrial injury in cardiovascular disease and Parkinson’s disease. The present study examined the effects of MitoQ on angiotensin II- (Ang II-) induced podocyte injury both in vivo and in vitro. Podocyte mitochondria in Ang II-infused mice exhibited morphological and functional alterations. The observed mitochondrial fragmentation and ROS production were alleviated with MitoQ treatment. In vitro, alterations in mitochondrial morphology and function in Ang II-stimulated podocytes, including mitochondrial membrane potential reduction, ROS overproduction, and adenosine triphosphate (ATP) deficiency, were significantly reversed by MitoQ. Moreover, MitoQ rescued the expression and translocation of Nrf2 (nuclear factor E2-related factor 2) and decreased the expression of Keap1 (Kelch-like ECH-associated protein 1) in Ang II-stimulated podocytes. Nrf2 knockdown partially blocked the protective effects of MitoQ on Ang II-induced mitochondrial fission and oxidative stress in podocytes. These results demonstrate that MitoQ exerts a protective effect in Ang II-induced mitochondrial injury in podocytes via the Keap1-Nrf2 signaling pathway.

scholarly journals Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Liu Ye ◽  
Qi Zeng ◽  
Maoyao Ling ◽  
Riliang Ma ◽  
Haishao Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Ventilator Induced Lung Injury ◽  
Nlrp3 Inflammasome Activation

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

Abstract 38: Endoplasmic Reticulum Stress Pathway-mediated Apoptosis is Involved in Ang II Induced Abdominal Aortic Aneurysm

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Yanwen Qin ◽  
Xu Cao ◽  
Ou Liu ◽  
Huihua Li ◽  
Hongjia Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Apolipoprotein E ◽  
Er Stress ◽  
Aortic Aneurysms ◽  
Aortic Diameter ◽  
Ang Ii ◽  
Caspase 12 ◽  
Abdominal Aortic ◽  
Deficient Mice

Backgroud— Abdominal aortic aneurysms (AAA) represent a unique and dramatic example of vessel wall remodeling characterized by degeneration of the elastic media. Apoptosis of vascular smooth muscle cells plays an important role in the pathogenesis of AAA. However, the potential mechanism remains poorly understood. Endoplasmic reticulum stress (ER stress)-induced apoptosis has been proved to be one of the important pathogenesis of cardiovascular disease. However, whether ER stress is involved in AAA is still not known. We assessed the hypothesis that ER-associated apoptosis is involved in Angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient mice. Methods and Results— Mice were infused with Ang II (1000 ng/kg per minute) with or without ER stress inhibitor (taurine-conjugated ursodeoxycholic acid) for 4 weeks. Mice infused with Ang II displayed an increase in aortic diameter. Detection of apoptosis was performed with the TUNEL assay. We performed Western blot and Real-time PCR to analyze indicators of ER molecule chaperone and ER-associated apoptosis. Glucose Regulated Proteins 78 and 94 (GRP78/BiP and GRP94), the ER chaperone, were up-regulated significantly in AAA compared to control. Furthermore, the hallmarks of ER-associated apoptosis, C/EBP homologous protein (CHOP), caspase-12 and PERK-eIF2-ATF4 signaling pathway were found to have activated in the AAA. The inhibition of ER stress significantly decreased maximal aortic diameter by 31% and abdominal aortic weight by 35% ( P <0.05, respectively). ER stress inhibitor also reduced GRP 78, CHOP and caspase-12 expression ( P <0.05, respectively). Taken together, these results suggested that apoptosis induced by ER stress may contribute to the development of AAA. Conclusions— ER stress response is involved in the pathogenesis of Ang II induced AAA in apolipoprotein E-deficient mice. ER stress inhibition attenuates AAA formation during Ang II infusion in apolipoprotein E-deficient mice. Therefore, ER stress could be a potential target for AAA.

scholarly journals Nlrp3 Deficiency Alleviates Angiotensin II-Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yu Chen ◽  
Meiying Zeng ◽  
Yang Zhang ◽  
Hui Guo ◽  
Wei Ding ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Gene Deletion ◽  
Cardiac Fibrosis ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Nlrp3 Gene ◽  
Nlrp3 Inflammasome Activation

Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3-/- mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson’s trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.

scholarly journals Mito-TEMPO Alleviates Renal Fibrosis by Reducing Inflammation, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Yuqing Liu ◽  
Yundan Wang ◽  
Wei Ding ◽  
Yingdeng Wang
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Renal Fibrosis ◽  
Oxidative Stress Markers ◽  
Stress Markers

Background. Renal fibrosis is a common pathological symptom of chronic kidney disease (CKD). Many studies support that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in the pathogenesis of CKD. In our study, we investigated the benefits and underlying mechanisms of Mito-TEMPO on renal fibrosis in 5/6 nephrectomy mice. Methods. Mice were randomly divided into five groups as follows: control group, CKD group, CKD + Mito-TEMPO (1 mg·kg−1·day−1) group, CKD + Mito-TEMPO (3 mg·kg−1·day−1) group, and Mito-TEMPO group (3 mg·kg−1·day−1). Renal fibrosis was evaluated by PAS, Masson staining, immunohistochemistry, and real-time PCR. Oxidative stress markers such as SOD2 activity and MDA level in serum and isolated mitochondria from renal tissue were measured by assay kits. Mitochondrial superoxide production was evaluated by MitoSOX staining and Western blot. Mitochondrial dysfunction was assessed by electron microscopy and real-time PCR. ER stress-associated protein was measured by Western blot. Results. Impaired renal function and renal fibrosis were significantly improved by Mito-TEMPO treatment. Furthermore, inflammation cytokines, profibrotic factors, oxidative stress markers, mitochondrial dysfunction, and ER stress were all increased in the CKD group. However, these effects were significantly ameliorated in the Mito-TEMPO treatment group. Conclusions. Mito-TEMPO ameliorates renal fibrosis by alleviating mitochondrial dysfunction and endoplasmic reticulum stress possibly through the Sirt3-SOD2 pathway, which sheds new light on prevention of renal fibrosis in chronic kidney disease.

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