scholarly journals (Pro)renin Receptor in Kidney Development and Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Renfang Song ◽  
Ihor V. Yosypiv
Keyword(s):  
Molecular Mechanisms ◽  
Kidney Development ◽  
Critical Role ◽  
Renin Angiotensin System ◽  
Vascular Abnormalities ◽  
Genes Encoding ◽  
Duplicated Collecting System ◽  
Renal Tubular ◽  
Renal Vascular

The renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the developing metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans are associated with a broad spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). These forms of CAKUT include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, and aberrant glomerulogenesis. Emerging evidence indicates that (pro)renin receptor (PRR), a novel component of the RAS, is essential for proper kidney development and that aberrant PRR signaling is causally linked to cardiovascular and renal disease. This paper describes the role of the RAS in kidney development and highlights emerging insights into the cellular and molecular mechanisms by which the PRR may regulate this critical morphogenetic process.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

2020 ◽  
Vol 17 (4) ◽  
pp. 394-401
Author(s):  
Yuanhua Wu ◽  
Yuan Huang ◽  
Jing Cai ◽  
Donglan Zhang ◽  
Shixi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Activity ◽  
Ht22 Cells ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

2021 ◽  
Author(s):  
Hongsheng Wang ◽  
Wanpeng Cui ◽  
Wenbing Chen ◽  
Fang Liu ◽  
Zhaoqi Dong ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Coping With Stress ◽  
Chemical Genetic ◽  
Chronic Social Defeat Stress ◽  
Ventral Tegmental ◽  
Laterodorsal Tegmentum ◽  
Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

The renin-angiotensin system in kidney development: role of COX-2 and adrenal steroids

2004 ◽  
Vol 181 (4) ◽  
pp. 549-559 ◽  
Author(s):  
B. L. Jensen ◽  
J. Stubbe ◽  
K. Madsen ◽  
F. T. Nielsen ◽  
O. Skott
Keyword(s):  
Kidney Development ◽  
Renin Angiotensin System ◽  
Adrenal Steroids ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Cox 2

Abstract 636: Gut Microflora Influences Pathology in the Kawasaki Disease (KD) Vasculitis Mouse Model

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Daiko Wakita ◽  
Yosuke Kurashima ◽  
Yoshihiro Takasato ◽  
Youngho Lee ◽  
Kenichi Shimada ◽  
...  
Keyword(s):  
Mouse Model ◽  
Immune Responses ◽  
Critical Role ◽  
Gut Microflora ◽  
Vascular Abnormalities ◽  
Coronary Arteritis ◽  
Specific Pathogen ◽  
New Perspective ◽  
Bacteria And Fungi

Background: KD is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated. Objective: To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model. Methods and Results: We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal bacteria and/or fungi, and determined whether altered microorganism burden in this KD mouse model contributes to disease severity. To deplete bacteria and/or fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to antibiotics cocktail (Abx) or antifungal drug (fluconazole; Fluc) in their drinking water for 5 wks and induced KD. The mice treated with Abx or Fluc had significantly reduced coronary arteritis and AAA compared to controls. The Abx plus Fluc administration showed marked decrease of KD vasculitis. Conclusions: We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that both bacteria and fungi in the intestinal microbiota may control the induction and severity of KD vasculitis. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.

scholarly journals Receptor Tyrosine Kinases in Kidney Development

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Renfang Song ◽  
Samir S. El-Dahr ◽  
Ihor V. Yosypiv
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Receptor Tyrosine Kinases ◽  
Adaptor Proteins ◽  
Downstream Signaling ◽  
Arterial Blood ◽  
Intracellular Signal ◽  
Human Birth

The kidney plays a fundamental role in the regulation of arterial blood pressure and fluid/electrolyte homeostasis. As congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common human birth defects, improved understanding of the cellular and molecular mechanisms that lead to CAKUT is critical. Accumulating evidence indicates that aberrant signaling via receptor tyrosine kinases (RTKs) is causally linked to CAKUT. Upon activation by their ligands, RTKs dimerize, undergo autophosphorylation on specific tyrosine residues, and interact with adaptor proteins to activate intracellular signal transduction pathways that regulate diverse cell behaviours such as cell proliferation, survival, and movement. Here, we review the current understanding of role of RTKs and their downstream signaling pathways in the pathogenesis of CAKUT.

scholarly journals Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism

2011 ◽  
Vol 301 (3) ◽  
pp. H903-H911 ◽  
Author(s):  
Kanchana Karuppiah ◽  
Lawrence J. Druhan ◽  
Chun-an Chen ◽  
Travis Smith ◽  
Jay L. Zweier ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Oxidase Activity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Caveolin 1 ◽  
Calcium Calmodulin Dependent ◽  
Enos Uncoupling ◽  
Nadph Oxidation ◽  
Interfering Rna

In the vasculature, nitric oxide (NO) is generated by endothelial NO synthase (eNOS) in a calcium/calmodulin-dependent reaction. In the absence of the requisite eNOS cofactor tetrahydrobiopterin (BH4), NADPH oxidation is uncoupled from NO generation, leading to the production of superoxide. Although this phenomenon is apparent with purified enzyme, cellular studies suggest that formation of the BH4 oxidation product, dihydrobiopterin, is the molecular trigger for eNOS uncoupling rather than BH4 depletion alone. In the current study, we investigated the effects of both BH4 depletion and oxidation on eNOS-derived superoxide production in endothelial cells in an attempt to elucidate the molecular mechanisms regulating eNOS oxidase activity. Results demonstrated that pharmacological depletion of endothelial BH4 does not result in eNOS oxidase activity, whereas BH4 oxidation gave rise to significant eNOS-oxidase activity. These findings suggest that the endothelium possesses regulatory mechanisms, which prevent eNOS oxidase activity from pterin-free eNOS. Using a combination of gene silencing and pharmacological approaches, we demonstrate that eNOS-caveolin-1 association is increased under conditions of reduced pterin bioavailability and that this sequestration serves to suppress eNOS uncoupling. Using small interfering RNA approaches, we demonstrate that caveolin-1 gene silencing increases eNOS oxidase activity to 85% of that observed under conditions of BH4 oxidation. Moreover, when caveolin-1 silencing was combined with a pharmacological inhibitor of AKT, BH4 depletion increased eNOS-derived superoxide to 165% of that observed with BH4 oxidation. This study identifies a critical role of caveolin-1 in the regulation of eNOS uncoupling and provides new insight into the mechanisms through which disease-associated changes in caveolin-1 expression may contribute to endothelial dysfunction.

scholarly journals Tubuloglomerular Disease With Cone-Shaped Epiphyses Associated With Hypomorphic Variant and a Novel p.Cys14Arg in the TTC21B Gene: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Martin Bezdíčka ◽  
Dana Zemková ◽  
Sylva Skálová ◽  
Eva Hovorková ◽  
Miroslav Podhola ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Development ◽  
Kidney Biopsy ◽  
Intraflagellar Transport ◽  
X Ray ◽  
Heterozygous Variant ◽  
Renal Tubular ◽  
Nephrotic Range Proteinuria ◽  
Generation Sequencing

Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.

scholarly journals Single-Cell Transcriptomic Analysis Revealed a Critical Role of SPP1/CD44-Mediated Crosstalk Between Macrophages and Cancer Cells in Glioma

2021 ◽  
Vol 9 ◽  
Author(s):  
Cong He ◽  
Luoyan Sheng ◽  
Deshen Pan ◽  
Shuai Jiang ◽  
Li Ding ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Heterogeneity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cell Communication ◽  
High Grade Glioma ◽  
Sequencing Analysis ◽  
High Grade ◽  
Cellular Components

High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.

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