Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

Tokinoya, Katsuyuki; Sekine, Nanami; Aoki, Kai; Ono, S.; Kuji, Tomoaki; Sugasawa, Takehito; Yoshida, Yasuko; Takekoshi, Kazuhiro

doi:10.3892/mmr.2021.11849

Cited by 11 publications

(24 citation statements)

References 32 publications

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“…This suggests the possibility that if RNLS activates PMCA4b, NO accumulation could be reduced, leading to less severe injury or more rapid recovery. NF-κB-regulated RNLS expression has also been shown to cause increased phosphorylation of AKT through a PMCA4b-dependent mechanism [58]. In B16-F10 cells, PMCA4b was also found to have a key role in RNLS-dependent ERK and STAT3 phosphorylation [11].…”

Section: Rnls Stimulates Distinct Intracellular Signalsmentioning

confidence: 99%

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Renalase: A Multi-Functional Signaling Molecule with Roles in Gastrointestinal Disease

Pointer

Gorelick

Desir

2021

Cells

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The survival factor renalase (RNLS) is a recently discovered secretory protein with potent prosurvival and anti-inflammatory effects. Several evolutionarily conserved RNLS domains are critical to its function. These include a 20 aa site that encodes for its prosurvival effects. Its prosurvival effects are shown in GI disease models including acute cerulein pancreatitis. In rodent models of pancreatic cancer and human cancer tissues, increased RNLS expression promotes cancer cell survival but shortens life expectancy. This 37 kD protein can regulate cell signaling as an extracellular molecule and probably also at intracellular sites. Extracellular RNLS signals through a specific plasma membrane calcium export transporter; this interaction appears most relevant to acute injury and cancer. Preliminary studies using RNLS agonists and antagonists, as well as various preclinical disease models, suggest that the immunologic and prosurvival effects of RNLS will be relevant to diverse pathologies that include acute organ injuries and select cancers. Future studies should define the roles of RNLS in intestinal diseases, characterizing the RNLS-activated pathways linked to cell survival and developing therapeutic agents that can increase or decrease RNLS in relevant clinical settings.

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Section: Rnls Stimulates Distinct Intracellular Signalsmentioning

confidence: 99%

“…It is suggested that this hepatocyte dysfunction and hepatic fibrosis progression could be connected to the absence of RNLS. Additionally, the absence of RNLS may cause an increase in oxidative stress and bring on macrophage infiltration in these tissues [58].…”

Section: Othersmentioning

confidence: 99%

Renalase: A Multi-Functional Signaling Molecule with Roles in Gastrointestinal Disease

Pointer

Gorelick

Desir

2021

Cells

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“…A theoretically similar approach, by direct targeting of the molecular mechanisms that underlie EMT, has been suggested as a novel opportunity for an effective anti-fibrotic therapy ( 38 , 85 , 97 ). Finally, the related research of renalase’s effects on fibrosis markers in the liver-injury mouse model ( 19 ) further confirms that the lack of the renalase gene favors oxidative stress promotion, significant macrophage accumulation, as discussed, and increased TGF-β expression, finally emerging as liver fibrosis progression. A schematic view of the TGF-β-mediated activation of non-canonical pathways with respect to signaling arms that may be targeted by renalase is depicted in Figure 1 , and a summary of current experimental evidence is presented in Table 1 .…”

Section: The Identification Of Renalase As a Relevant Antifibrotic Mo...mentioning

confidence: 66%

“…Additional studies provided evidence that renalase’s distribution is spread far beyond the kidneys and heart. Therefore, its tissue expression pattern, to varying extents, is revealed in the liver ( 19 , 44 ), small intestines ( 45 ), skeletal muscles ( 46 ), pancreas ( 22 , 47 ), cornea ( 48 ), brain and peripheral nerves ( 49 , 50 ), and malignant tissue as well ( 22 , 23 , 51 ), implying renalase’s remote role in general homeostasis and its possible relevant biologic activity. Accordingly, the latest research indicates a potential role for renalase in placental development and function, owing to its expression in the placenta throughout human gestation ( 25 ).…”

Section: Renalase’s Structure Expression and Cell Biologymentioning

confidence: 99%

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

Stojanović

Mitić

Stojanović

et al. 2022

Front. Cardiovasc. Med.

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Cardiac fibrosis represents a redundant accumulation of extracellular matrix proteins, resulting from a cascade of pathophysiological events involved in an ineffective healing response, that eventually leads to heart failure. The pathophysiology of cardiac fibrosis involves various cellular effectors (neutrophils, macrophages, cardiomyocytes, fibroblasts), up-regulation of profibrotic mediators (cytokines, chemokines, and growth factors), and processes where epithelial and endothelial cells undergo mesenchymal transition. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. The most effective anti-fibrotic strategy will have to incorporate the specific targeting of the diverse cells, pathways, and their cross-talk in the pathogenesis of cardiac fibroproliferation. Additionally, renalase, a novel protein secreted by the kidneys, is identified. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase’s compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-α, IL-6, MCP-1, MIP-2, ROS, TGF-β1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins (1 and 3) activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression (’α-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. This review provides the scientific rationale for renalase’s scrutiny regarding cardiac fibrosis, and there is great anticipation that these newly identified pathways are set to progress one step further. Although substantial progress has been made, indicating renalase’s therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase, concerning cardiac fibrosis, before any potential translation to clinical investigation.

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“…α-SMA expression in HSCs could also be lowered through overexpression of cytochrome P450 omega-hydroxylase 4a14 (CYP4A14) 95 or through knock-out of renalase (an oxidative stress suppressor) in NASH mice 96 . Inhibition of focal adhesion kinase reduced α-SMA and collagen overexpression in an animal model, in the presence of TGFβ 20 (Table 2).…”

Section: Cytoskeleton Protein In Nafld Diagnosismentioning

confidence: 99%

Cytoskeleton alterations in non-alcoholic fatty liver disease

Pessoa

Teixeira

2022

Metabolism

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Background: Due to its extremely high prevalence and severity, non-alcoholic fatty liver disease (NALFD) is a serious health and economic concern worldwide.Developing effective methods of diagnosis and therapy demands a deep understanding of its molecular basis. One of the strategies in such an endeavor is the analysis of alterations in the morphology of liver cells. Such alterations, widely reported in NAFLD patients and disease models, are related to the cytoskeleton. Therefore, the fate of the cytoskeleton components is useful to uncover the molecular basis of NAFLD, to further design innovative approaches for its diagnosis and therapy.Main findings: Several cytoskeleton proteins are up-regulated in liver cells of NAFLD patients. Under pathological conditions, keratin 18 is released from hepatocytes and its detection in the blood emerges as a non-invasive diagnosis tool. α-Smooth muscle actin is up-regulated in hepatic stellate cells and its downregulation has been widely tested as a potential NALFD therapeutic approach.Other cytoskeleton proteins, such as vimentin, are also up-regulated.Conclusions: NAFLD progression involves alterations in expression levels of proteins that build the liver cytoskeleton or associate with it. These findings provide a timely opportunity of developing novel approaches for NAFLD diagnosis and therapy.

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Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model

Cited by 11 publications

References 32 publications

Renalase: A Multi-Functional Signaling Molecule with Roles in Gastrointestinal Disease

Renalase: A Multi-Functional Signaling Molecule with Roles in Gastrointestinal Disease

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

Cytoskeleton alterations in non-alcoholic fatty liver disease

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