Reduced expression of VAChT increases renal fibrosis

Silva, Reinaldo Correia; Terra, Fernanda Fernandes; Guise, Yuri Felipe Souza; Prado, Marco A. M.; Prado, Vânia F.; Hiyane, Meire Ioshie; Malheiros, Denise Maria Avancini Costa; Prado, Carla M.; Câmara, Niels Olsen Saraiva; Braga, Tárcio Teodoro

doi:10.1016/j.pathophys.2016.07.002

Cited by 7 publications

(7 citation statements)

References 47 publications

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“…Although the global VAChT‐KD homozygous mice [17], which also show neuromuscular deficits, can be used as a tool to study the impact of ACh release on neuromuscular function, the systemic effects observed in VAChT‐KD homozygous mice, including renal and cardiac deficiencies [24,25], are major confounders for the analysis of behavioral deficits. As VAChT expression is abolished selectively in alpha‐MNs, neuromuscular deficits can be clearly ascertained in the mnVAChT KD mouse model.…”

Section: Discussionmentioning

confidence: 99%

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Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

et al. 2021

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Motoneurons (MNs) control muscle activity by releasing the neurotransmitter acetylcholine (ACh) at the level of neuromuscular junctions. ACh is packaged into synaptic vesicles by the vesicular ACh transporter (VAChT), and disruptions in its release can impair muscle contraction, as seen in congenital myasthenic syndromes (CMS). Recently, VAChT gene mutations were identified in humans displaying varying degrees of myasthenia. Moreover, mice with a global deficiency in VAChT expression display several characteristics of CMS. Despite these findings, little is known about how a long‐term decrease in VAChT expression in vivo affects MNs structure and function. Using Cre‐loxP technology, we generated a mouse model where VAChT is deleted in select groups of MNs (mnVAChT‐KD). Molecular analysis revealed that the VAChT deletion was specific to MNs and affected approximately 50% of its population in the brainstem and spinal cord, with alpha‐MNs primarily targeted (70% in spinal cord). Within each animal, the cell body area of VAChT‐deleted MNs was significantly smaller compared to MNs with VAChT preserved. Likewise, muscles innervated by VAChT‐deleted MNs showed atrophy while muscles innervated by VAChT‐containing neurons appeared normal. In addition, mnVAChT KD mice had decreased muscle strength, were hypoactive, leaner and exhibited kyphosis. This neuromuscular dysfunction was evident at 2 months of age and became progressively worse by 6 months. Treatment of mutants with a cholinesterase inhibitor was able to improve some of the motor deficits. As these observations mimic what is seen in CMS, this new line could be valuable for assessing the efficacy of potential CMS drugs.

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Section: Discussionmentioning

confidence: 99%

“…One example is the VAChT‐KD model, where mice have a global decrease in VAChT expression [18]. VAChT‐KD mice are myasthenic and display neuromuscular alterations [17,22,23], as well as cognitive impairments [17], visceral organ dysfunctions [24–26], and increased inflammatory responses [27].…”

Section: Introductionmentioning

confidence: 99%

Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

et al. 2021

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“…CD4 + T cells can differentiate into three subpopulations, the Th1, Th2, and Th17 subsets [18]. The pivotal role of Th2 cells versus the classic role of Th1 cells was recently highlighted, and the Th17 response was also enhanced in the UUO model [19][20][21]. These studies indicated that renal interstitial injury could be improved by interfering with the polarization of CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4⁺ T Cell Polarization

Zhu

Chen

Xian

et al. 2020

Stem Cells International

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Purpose. Recent evidence has shown that CD4+ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4+ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4+ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4+ T cells in vitro. Materials and Methods. We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4+ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4+ T cells by enzyme-linked immunosorbent assay (ELISA). Results. Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3+ cell infiltration, with a significantly decreased IL17A+CD4+ T cell/CD4+ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4+ T cells were cocultured with PMSCs, CD4+IL17A+ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P<0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P<0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3+/IL-17+ cell infiltration was increased in the kidneys of UUO model animals on day 7. Conclusions. PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4+ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.

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“…PNU-282987 is a highly selective α7nAChR agonist and MLA is a selective and potent antagonist of α7nAChR. The doses of these drugs were determined based on the conversion of dosages used in other experiments [ 38 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis

Hao

Liu

Guo

2022

Reprod Biol Endocrinol

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Background Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the progression of endometriosis in mice. Extensive research also has shown that the activation of the cholinergic anti-inflammatory pathway by VNS activates α7 nicotinic acetylcholine receptor (α7nAChR), potently reducing inflammation. Yet whether α7nAChR plays any role in endometriosis is unknown. We evaluated its expression in normal endometrium, ovarian and deep endometriotic lesions, and evaluated its role in the development of endometriosis. Methods Immunohistochemistry analyses of α7nAChR in endometriotic lesions as well as control endometrium, and quantification of tissue fibrosis by Masson trichrome staining were performed. Mouse experiments were conducted to evaluate the impact of α7nAChR activation or suppression on lesional progression and possible therapeutic effect. Finally, in vitro experiments were conducted to evaluate the effect of activation of α7nAChR on epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in an endometriotic epithelial cell line and primary endometriotic stromal cells derived from ovarian endometrioma tissue samples. Results Immunostaining of α7nAChR was significantly reduced in human endometriotic epithelial cells as compared with their counterpart in normal endometrium. Lesional α7nAChR staining levels correlated negatively with lesional fibrosis and the severity of dysmenorrhea. The α7nAChR agonist significantly impeded the development of endometriotic lesions in mouse models possibly through hindrance of EMT and FMT. It also demonstrated therapeutic effects in mice with induced deep endometriosis. Treatment of endometriotic epithelial and stromal cells with an α7nAChR agonist significantly abrogated platelet-induced EMT, FMT and SMM, and suppressed cellular contractility and collagen production. Conclusions α7nAChR is suppressed in endometriotic lesions, and its activation by pharmacological means can impede EMT, FMT, SMM, and fibrogenesis of endometriotic lesions. As such, α7nAChR can be rightfully viewed as a potential target for therapeutic invention. Trial registration Not applicable.

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Reduced expression of VAChT increases renal fibrosis

Cited by 7 publications

References 47 publications

Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4⁺ T Cell Polarization

Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis

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Reduced expression of VAChT increases renal fibrosis

Cited by 7 publications

References 47 publications

Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

Motoneuron‐specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome

Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4+ T Cell Polarization

Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis

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Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4⁺ T Cell Polarization