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

Pointer, Thomas C; Gorelick, Fred S.; Desir, Gary V.

doi:10.3390/cells10082006

Cited by 17 publications

(61 citation statements)

References 75 publications

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“…RNLS expression within trophoblasts throughout placental development in placental villi, decidua, and fetal membranes, suggests a potential role for RNLS in trophoblast function. Multiple isoforms of RNLS have been detected in various tissues, although their exact roles are unclear (reviewed in Pointer, Gorelick and Desir, 2021) 27 . Interestingly, multiple RNLS isoforms were expressed in placental tissue, with one unique to the decidua.…”

Section: Discussionmentioning

confidence: 99%

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Wang

Silva

Toothaker

et al. 2022

Sci Rep

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Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase’s role in normal and diseased human placenta.

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Section: Discussionmentioning

confidence: 99%

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Wang

Silva

Toothaker

et al. 2022

Sci Rep

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“…To date, it has not been shown whether rs11202702 SNP affects RNLS gene expression. RNLS can activate AKT [50] which activates the Wnt/βcatenin signaling pathway [51] (therefore, it can consequently lead to an increase in TG transcription [26]).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels

Pleić

Leko

Gunjača

et al. 2022

IJMS

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Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10−8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.

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“…The concept of renalase’s pathophysiological relevance spurred the identification of its biochemical and pathophysiological nature, providing the following conclusions. The human renalase gene is located on chromosome 10, and it contains 11 exons ( 10 , 42 , 43 ). There are two major isoforms of renalase in humans, known as renalase 1, and 2 ( 52 ), and two more isoforms (3 and 4), that lack oxidase function activity due to their significantly shortened amine oxidase domains ( 10 , 13 , 43 ).…”

Section: Renalase’s Structure Expression and Cell Biologymentioning

confidence: 99%

“…Additionally, renalase, a novel protein secreted by the kidneys, is identified. Mounting evidence demonstrates the cytoprotective properties of this innovative molecule, establishing it as a key survival element in various organ injuries, and tumors, in gestation, and, more importantly, as a significant anti-fibrotic factor ( 10 – 25 ). There has been a significant breakthrough over the past few years, and is currently in progress, in understanding renalase’s pathophysiology, and its experimentally ( in vivo and in vitro ) demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses.…”

Section: Introductionmentioning

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

Cited by 17 publications

References 75 publications

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation

Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels

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

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