Relaxin and fibrosis: Emerging targets, challenges, and future directions

Konieczko, Elisa M.; Bennett, Robert G.; Samuel, Chrishan S.; Royce, Simon G.

doi:10.1016/j.mce.2019.02.005

Cited by 18 publications

(14 citation statements)

References 85 publications

(111 reference statements)

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“…A total of 40 signaling pathways were identified. In the most significantly altered signaling pathway in this study, fibrosis was reported in previous studies to be involved in the ‘Hedgehog signaling pathway’ ( 35 – 37 ), ‘ABC transporters’ ( 38 ), ‘ErbB signaling pathway’ ( 39 , 40 ), ‘cAMP signaling pathway’ ( 41 , 42 ), ‘Relaxin signaling pathway’ ( 43 , 44 ), ‘Ras signaling pathway’ ( 45 , 46 ) and ‘PI3K-Akt signaling pathway’ ( 47 , 48 ). Additionally, six ECM-associated pathways were directly associated with renal fibrosis.…”

Section: Discussionmentioning

confidence: 54%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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in acute aristolochic acid nephropathy (aan), aristolochic acid (aa) induces renal injury and tubulointerstitial fibrosis. However, the roles of micrornas (mirnas/mirs) and mrnas involved in aan are not clearly understood. The aim of the present study was to examine aa-induced genome-wide differentially expressed (de) mirnas and de mrnas using deep sequencing in mouse kidneys, and to analyze their regulatory networks. in the present self-controlled study, mice were treated with 5 mg/kg/day aa for 5 days, following unilateral nephrectomy. AA-induced renal injury and tubulointerstitial fibrosis were detected using hematoxylin and eosin staining and Masson's trichrome staining in the mouse kidneys. a total of 82 DE miRNAs and 4,605 DE mRNAs were identified between the aa-treated group and the self-control group. of these de mirnas and mrnas, some were validated using reverse transcription-quantitative Pcr. expression levels of the profibrotic miR-21, miR-433 and miR-132 families were significantly increased, whereas expression levels of the anti-fibrotic miR-122-5p and let-7a-1-3p were significantly decreased. Functions and signaling pathways associated with the de mirnas and mrnas were analyzed using Gene ontology and Kyoto encyclopedia of Genes and Genomes (KeGG). a total of 767 de pairs (in opposing directions) of mirnas and their mrna targets were identified. among these, regulatory networks of mirnas and mrnas were analyzed using KeGG to identify enriched signaling pathways and extracellular matrix-associated pathways. in conclusion, the present study identified genome-wide de mirnas and mrnas in the kidneys of aa-treated mice, as well as their regulatory pairs and signaling networks. The present results may improve the understanding of the role of de mirnas and their mrna targets in the pathophysiology of acute aan.

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Section: Discussionmentioning

confidence: 54%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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“…But we have not been able to examine the efficacy of RLX-2 on pre-existing fibrosis. RLX-2 is expected to use in various fibrous diseases [11], and is also known to enhance heart function with dilating peripheral blood vessels, and clinical research was held as a therapeutic agent for heart failure [46]. Although further study is needed, RLX-2 can be expected to be a new therapy for endometriosis with various effects.…”

Section: Discussionmentioning

confidence: 99%

“…In the endometriosis mouse model (Figure 5a), administration of RLX-2 significantly decreased the area of the endometriotic-like lesion compared to the non-treated control (p = 0.01, Figure 5b). As RLX-2 has an anti-fibrotic potential [11], the extent of fibrosis in the mouse endometriotic-like lesions was evaluated using the Masson trichrome staining method. As shown in Figure 5c, fibrous tissues, which are stained with light blue, were decreased in the RLX-2 group compared to the control.…”

Section: Endometriosis Mouse Model (Endometrial Implantation Mouse Momentioning

confidence: 99%

“…Recently, relaxin (RLX)-2 has attracted significant interest for its anti-fibrotic effect in various fibrous diseases of the heart, lungs, kidneys, and bladder [11]. RLX-2 is a peptide hormone belonging to the insulin superfamily that has a collagenolytic effect [11,12]. In women, RLX-2 is secreted from the corpus luteum and placenta, and the role of RLX-2 during labor has been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

“…However, the effect of RLX-2 on endometriosis remained unclear. Since RLX-2 has been shown to be a potential treatment for various fibrotic diseases [11], we conducted this study on the hypothesis that RLX-2 could be an effective treatment for endometriosis.…”

Section: Introductionmentioning

confidence: 99%

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Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation

et al. 2020

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Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% (p < 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control (p = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation.

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