scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

Erythropoietin in COVID-19-Induced Neuroinflammation; EPO Plus Losartan Might be Promising

2020 ◽  
Author(s):  
Reza Nejat ◽  
Ahmad Shahir Sadr ◽  
David Najafi
Keyword(s):  
Inflammatory Mediators ◽  
Renin Angiotensin System ◽  
Oxygen Species ◽  
Ang Ii ◽  
Angiotensin System ◽  
Intracellular Messengers ◽  
The Central Nervous System ◽  
Harmful Effects

Introduction: Neuroinflammation is the inflammatory reaction in the central nervous system (CNS) provoked by diverse insults. This phenomenon results in a cascade of release of inflammatory mediators and intracellular messengers such as reactive oxygen species. The elicited responses are the cause of many neurological and neurodegenerative disorders. Erythropoietin (EPO) has been considered effective in attenuating this inflammatory process in the CNS, yet its administration in COVID-19 needs meticulously designed studies. Discussion: Neuroinflammation in COVID-19 due to probable contribution of renin-angiotensin system dysregulation resulting in surplus of Ang II and owing to the synergistic interaction between this octapeptide and EPO needs special consideration. Both of these compounds increase intracellular Ca2+ which may induce release of cytokine and inflammatory mediators leading to aggravation of neuroinflammation. In addition, Ang II elevates HIF even in normoxia which by itself increases EPO. It is implicated that EPO and HIF may likely increase in patients with COVID-19 which makes administration of EPO to these patients hazardous. Furthermore, papain-like protease of SARS-CoV2 as a deubiquitinase may also increase HIF. Conclusion: It is hypothesized that administration of EPO to patients with COVID-19-induced neuroinflammation may not be safe and in case EPO is needed for any reason in this disease adding of losartan may block AT1R-mediated post-receptor harmful effects of Ang II in synergism with EPO. Inhibition of papain-like protease might additionally decrease HIF in this disease. More in vitro, in vivo and clinical studies are needed to validate these hypotheses.

scholarly journals Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1378-1385
Author(s):  
Chen-Min Sun ◽  
Wen-Yi Zhang ◽  
Shu-Yan Wang ◽  
Gang Qian ◽  
Dong-Liang Pei ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Target Gene ◽  
Rat Kidney ◽  
Inflammatory Factors ◽  
Strongly Correlated ◽  
Tnf Α ◽  
Function Loss

Abstract Aim Renal fibrosis (RF) is a common clinical condition leading to irreversible renal function loss. Tyrosine kinase proteins and microRNAs (miRs) are associated with pathogenesis and we aim to investigate the role of Fer and its partner miR(s) in RF. Method In silico reproduction of Mouse Kidney FibrOmics browser was performed to identify potential miR(s) and target gene(s). In vivo validation was performed in C57BL/6 mice with unilateral ureteral obstruction (UUO). In vitro validation was performed in rat kidney fibroblast NRK-49F cells. Mimics and inhibitors of miR-29c-3p were constructed. The target gene Fer was monitored by RT-PCR and western blotting. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in serum and media were measured by ELISA. Results The Fer expression and protein level were gradually increased during 14 days of UUO modeling. miR-29c-3p expression was strongly correlated with that of Fer. In vivo validation showed increased expressions of fibrosis-associated genes and increased phospoho-Smad3 level in the UUO model. Fer-knockdown (KD) significantly decreased expressions of fibrosis-associated genes. Pharmaceutical inhibition of Fer showed similar effects to miR-29c-3p, and miR inhibition showed a significant decrease of excretion of inflammatory factors. Conclusion Dysregulation of miR-29c-3p and Fer plays a role in RF. Pharmaceutical or genetic inhibition of Fer may serve as the potential treatment for RF.

Control of intestinal absorption by the renin-angiotensin system

1985 ◽  
Vol 249 (1) ◽  
pp. G3-G15 ◽  
Author(s):  
N. R. Levens
Keyword(s):  
Intestinal Absorption ◽  
Renin Angiotensin System ◽  
Sympathetic Nerves ◽  
Ang Ii ◽  
Volume Depletion ◽  
Angiotensin System ◽  
Dual Action ◽  
Dose Dependent

In vivo angiotensin II (ANG II) exerts a dose-dependent dual action upon intestinal absorption. At low doses, ANG II stimulates sodium (Na) and water absorption from all intestinal areas. At high doses, ANG II inhibits absorption. The stimulation of jejunal absorption in response to ANG II is secondary to the release of norepinephrine (NE) from enteric sympathetic nerves. ANG II may act either within the brain or at the sympathetic nerve terminal to liberate NE. In contrast, the inhibition of absorption in response to ANG II is due to enteric prostaglandin production. At the present time it is unclear whether the changes in absorption in response to ANG II in vivo are due to changes in transport processes or secondary to alterations in enteric hemodynamics. ANG II also exerts a dose-dependent dual action on intestinal ion and water absorption in vitro. The mechanisms responsible for changes in absorption in vitro are unknown. However, since enteric sympathetic nerves are severed from their ganglia, it is unlikely that ANG II stimulates absorption in isolated preparations through release of NE. ANG II exerts a major control over intestinal absorption following volume depletion. The hormone controls colonic absorption through release of aldosterone and directly influences jejunal absorption via enteric sympathetic nerves. ANG II may control ileal absorption following volume depletion. All components of the renin-angiotensin system are present within the intestine. Furthermore, ANG II-like immunoreactivity is present within enteric nerves. The role of locally formed ANG II in the control of intestinal absorption has not been studied. Models illustrating the effect of ANG II on intestinal absorption are discussed.

ANG II reduces net acid secretion in rat outer medullary collecting duct

2003 ◽  
Vol 285 (5) ◽  
pp. F930-F937 ◽  
Author(s):  
Susan M. Wall ◽  
Michael P. Fischer ◽  
Dawn M. Glapion ◽  
Mae De La Calzada
Keyword(s):  
Acid Secretion ◽  
Collecting Duct ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Acid Base Balance ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Medullary Collecting Duct

In rat outer medullary collecting duct (OMCD), the mechanism(s) and regulation of H+ secretion are not understood fully. The effect of changes in acid-base balance and the renin-angiotensin system on net H+ secretion was explored. Rats received NaCl, NaHCO3, NH4Cl, or nothing in their drinking water for 7 days. Total ammonia and total CO2 ( JtCO2) fluxes were measured in OMCD tubules perfused in vitro from rats in each treatment group. JtCO2 was reduced in tubules from rats drinking NH4Cl relative to those drinking NaHCO3. Because NH4Cl intake increases plasma renin and aldosterone, we asked if upregulation of the renin-angiotensin system reduces net H+ secretion. Deoxycorticosterone pivalate administered in vivo did not affect JtCO2. However, ANG II given in vivo at 0.1 ng/min reduced JtCO2 by 35%. To determine if ANG II has a direct effect on acid secretion, JtCO2 was measured with ANG II applied in vitro. ANG II (10-8 M) present in the bath solution reduced JtCO2 by 35%. This ANG II effect was not observed in the presence of the AT1 receptor blocker candesartan. In conclusion, in rat OMCD, JtCO2 is paradoxically reduced with NH4Cl ingestion. Increased circulating ANG II, as occurs during metabolic acidosis, reduces JtCO2.

scholarly journals The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382199528
Author(s):  
Qing Lv ◽  
Qinghua Xia ◽  
Anshu Li ◽  
Zhiyong Wang
Keyword(s):  
Tumor Microenvironment ◽  
Interleukin 1 ◽  
Mrna Level ◽  
Inflammatory Factors ◽  
Stomach Carcinoma ◽  
Downstream Target ◽  
Volume Weight

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

scholarly journals Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1912
Author(s):  
Kaushik Chakravarty ◽  
Victor G. Antontsev ◽  
Maksim Khotimchenko ◽  
Nilesh Gupta ◽  
Aditya Jagarapu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renin Angiotensin System ◽  
Mechanistic Modeling ◽  
Channel Blockers ◽  
Angiotensin System ◽  
In Silico Modeling ◽  
Site Of Action ◽  
Line Of Therapy

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.

scholarly journals A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

2017 ◽  
Vol 312 (5) ◽  
pp. H968-H979 ◽  
Author(s):  
Neeru M. Sharma ◽  
Shyam S. Nandi ◽  
Hong Zheng ◽  
Paras K. Mishra ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

Thermal responses to central angiotensin II, SQ 20881, and dopamine infusions in sheep

1985 ◽  
Vol 248 (3) ◽  
pp. R371-R377 ◽  
Author(s):  
B. S. Huang ◽  
M. J. Kluger ◽  
R. L. Malvin
Keyword(s):  
Angiotensin Ii ◽  
Body Temperature ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Significant Rise ◽  
Ang Ii ◽  
Deep Body Temperature ◽  
Angiotensin System ◽  
Conscious Sheep

The thermoregulatory role of brain angiotensin II (ANG II) was tested by intracerebroventricular (IVT) infusion of ANG II or the converting enzyme inhibitor SQ 20881 (SQ) in 15 conscious sheep. Deep body temperature decreased 0.30 +/- 0.07 degree C (SE) during the 3-h period of IVT ANG II (25 ng/min) infusion (P less than 0.05) and increased 0.50 +/- 0.13 degree C during IVT SQ (1 microgram/min) infusion (P less than 0.01). To determine whether the rise in body temperature after IVT SQ infusion might be the result of a central renin-angiotensin system (RAS), SQ was infused IVT in five conscious sheep 20 h after bilateral nephrectomy. This resulted in a significant rise in body temperature of 0.28 +/- 0.05 degree C (P less than 0.05). When vasopressin antidiuretic hormone (ADH) was infused intravenously at the same time of IVT SQ infusion, the rise in temperature was depressed, but ADH did not lower the temperature below basal. IVT dopamine (20 micrograms/min) increased body temperature by 0.40 +/- 0.04 degree C (P less than 0.01), which was qualitatively similar to the result with IVT SQ. These data support the hypothesis that endogenous brain ANG II may play a role in thermoregulation. Furthermore, plasma ADH level, regulated in part by brain ANG II, is probably not the mediator of that thermoregulation. The similar effects of IVT dopamine and SQ on body temperature strengthen the hypothesis that dopamine may be involved in the central action of brain ANG II.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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