scholarly journals N-acetyl-seryl-aspartyl-lysyl-proline Inhibits Diabetes-Associated Kidney Fibrosis and Endothelial-Mesenchymal Transition

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Takako Nagai ◽  
Megumi Kanasaki ◽  
Swayam Prakash Srivastava ◽  
Yuka Nakamura ◽  
Yasuhito Ishigaki ◽  
...  
Keyword(s):  
Ace Inhibitor ◽  
Receptor Expression ◽  
Fgf Receptor ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines-suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7.

scholarly journals Knockdown of LncRNA-H19 Ameliorates Kidney Fibrosis in Diabetic Mice by Suppressing miR-29a-Mediated EndMT

2020 ◽  
Vol 11 ◽  
Author(s):  
Sen Shi ◽  
Li Song ◽  
Hao Yu ◽  
Songlin Feng ◽  
Jianhua He ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Non Coding Rnas ◽  
Endothelial Mesenchymal Transition

Diabetic nephropathy is the leading cause of kidney fibrosis. Recently, altered expressed or dysfunction of some long non-coding RNAs (lncRNAs) has been linked to kidney fibrosis; however, the mechanisms of lncRNAs in kidney fibrosis remain unclear. We have shown that the DPP-4 inhibitor linagliptin can inhibit endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with DPP-4 protein levels via the induction of miR-29. Here, we found that expression of the lncRNA H19 was significantly up-regulated in TGF-β2-induced fibrosis in human dermal microvascular endothelial cells (HMVECs) in vitro, and in kidney fibrosis of streptozotocin-induced diabetic CD-1 mice. We also detected up-regulated H19 expression and down-regulated miR-29a expression in the early and advanced mouse models of diabetic kidney fibrosis. H19 knockdown significantly attenuated kidney fibrosis in vitro and in vivo, which was associated with the inhibition of the EndMT-associated gene FSP-1. We also found that the up-regulation of H19 observed in fibrotic kidneys associated with the suppression of miR-29a in diabetic mice. H19, miR-29a, and EndMT contribute to a regulatory network involved in kidney fibrosis, and are associated with regulation of the TGF-β/SMAD3 singling pathway. This study indicates that inhibition of LncRNA H19 represents a novel anti-fibrotic treatment for diabetic kidney diseases.

scholarly journals Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction

2019 ◽  
Vol 39 (10) ◽  
pp. 2168-2191 ◽  
Author(s):  
Bronson A. Haynes ◽  
Li Fang Yang ◽  
Ryan W. Huyck ◽  
Eric J. Lehrer ◽  
Joshua M. Turner ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Smooth Muscle Actin ◽  
Phenotypic Change ◽  
Alpha Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Endothelial To Mesenchymal Transition

Objective: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. Conclusions: We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.

scholarly journals Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium

2019 ◽  
Vol 216 (8) ◽  
pp. 1874-1890 ◽  
Author(s):  
Nicolas Ricard ◽  
Rizaldy P. Scott ◽  
Carmen J. Booth ◽  
Heino Velazquez ◽  
Nicholas A. Cilfone ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Cardiac Conduction ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Endothelin 1 ◽  
Endocrine Organs ◽  
Endothelial To Mesenchymal Transition

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1−/− mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

scholarly journals Antitumorigenic Effects of Inhibiting Ephrin Receptor Kinase Signaling by GLPG1790 against Colorectal Cancer Cell Lines In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Alessandro Colapietro ◽  
Giovanni Luca Gravina ◽  
Francesco Petragnano ◽  
Irene Fasciani ◽  
Bianca Maria Scicchitano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Receptor Expression ◽  
Mutant Form ◽  
Kinase Signaling ◽  
P53 Expression ◽  
Mesenchymal Transition ◽  
Hct116 Cells

Erythropoietin-producing hepatocellular receptors (Eph) promote the onset and sustain the progression of cancers such as colorectal cancer (CRC), in which the A2 subtype of Eph receptor expression has been shown to correlate with a poor prognosis and has been identified as a promising therapeutic target. Herein, we investigated, in vitro and in vivo, the effects of treatment with GLPG1790, a potent pan-Eph inhibitor. The small molecule has selective activity against the EphA2 isoform in human HCT116 and HCT15 CRC cell lines expressing a constitutively active form of RAS concurrently with a wild-type or mutant form of p53, respectively. GLPG1790 reduced EPHA2 phosphorylation/activation and induced G1/S cell-cycle growth arrest by downregulating the expression of cyclin E and PCNA, while upregulating p21Waf1/Cip1 and p27Cip/Kip. The inhibition of ephrin signaling induced quiescence in HCT15 and senescence in HCT116 cells. While investigating the role of CRC-related, pro-oncogenic p53 and RAS pathways, we found that GLPG1790 upregulated p53 expression and that silencing p53 or inhibiting RAS (human rat sarcoma)/ERKs (extracellular signal-regulated kinase) signaling restrained the ability of GLPG1790 to induce senescence in HCT116 cells. On the other hand, HCT15 silencing of p53 predisposed cells to GLPG1790-induced senescence, whilst no effects of ERK inhibition were observed. Finally, GLPG1790 hindered the epithelial-mesenchymal transition, reduced the migratory capacities of CRC, and affected tumor formation in xenograft models in vivo more efficiently using HCT116 than HCT15 for xenografts. Taken together, our data suggest the therapeutic potential of GLPG1790 as a signal transduction-based therapeutic strategy in to treat CRC.

scholarly journals Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice

2015 ◽  
Vol 112 (27) ◽  
pp. 8421-8426 ◽  
Author(s):  
Luca Bravi ◽  
Noemi Rudini ◽  
Roberto Cuttano ◽  
Costanza Giampietro ◽  
Luigi Maddaluno ◽  
...  
Keyword(s):  
Vascular Malformations ◽  
Pharmacological Therapy ◽  
Bmp Signaling ◽  
Mesenchymal Transition ◽  
Transcription Activity ◽  
Recommended Treatment ◽  
The Central Nervous System ◽  
Endothelial To Mesenchymal Transition

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell–selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor–independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin–driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

scholarly journals In Vitro and In Vivo Models to Study Corneal Endothelial-mesenchymal Transition

10.3791/54329 ◽  
2016 ◽  
Author(s):  
Wei-Ting Ho ◽  
Chien-Chia Su ◽  
Jung-Shen Chang ◽  
Shu-Wen Chang ◽  
Fung-Rong Hu ◽  
...  
Keyword(s):  
Mesenchymal Transition ◽  
Endothelial Mesenchymal Transition

scholarly journals PP2A phosphatase inhibition is anti-fibrotic through Ser77 phosphorylation-mediated ARNT/ARNT homodimer formation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gunsmaa Nyamsuren ◽  
Gregor Rapp ◽  
Hassan Dihazi ◽  
Elisabeth M. Zeisberg ◽  
Desiree Tampe ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Receptor Expression ◽  
Kidney Cells ◽  
Murine Models ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Human Embryonic Kidney Cells ◽  
Aryl Hydrocarbon

AbstractAryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT–ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. Here, we demonstrate that phosphorylation of the Ser77 residue is critical for ARNT–ARNT homodimer formation and stabilization. We further demonstrate that inhibition of PP2A phosphatase activity by LB100 enhances ARNT–ARNT homodimers both in vivo and in vitro (mouse tubular epithelial cells and human embryonic kidney cells). In murine models of kidney fibrosis, and also of liver fibrosis, combinations of FK506 or GPI1046 (to induce ARNT expression) with LB100 (to enhance ARNT homodimerization) elicit additive anti-fibrotic activities. Our study provides additional evidence for the anti-fibrotic activity of ARNT–ARNT homodimers and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.

scholarly journals Melatonin Promotes Heterotopic Ossification Through Regulation of Endothelial-Mesenchymal Transition in Injured Achilles Tendons in Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Jie Zhang ◽  
Jiajun Tang ◽  
Jie Liu ◽  
Bo Yan ◽  
Bin Yan ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Healing Process ◽  
Marker Gene ◽  
Underlying Mechanism ◽  
Heterotopic Bone ◽  
Mesenchymal Transition ◽  
Gene And Protein Expression ◽  
Endothelial Mesenchymal Transition

Although heterotopic ossification (HO) has been reported to be a common complication of the posttraumatic healing process, the underlying mechanism remains unknown. Endothelial-mesenchymal transition (EndMT) is known to play a role in HO, and our recent study observed that neuroendocrine signals can promote HO by modulating EndMT. Melatonin, a neuroendocrine hormone secreted mainly by the pineal gland, has been documented to perform its function in the skeletal system. This study aimed at describing the expression of melatonin during the formation of HO in rat models of Achilles tendon injury and to further investigate its role in regulating EndMT in HO. Histological staining revealed the expression of melatonin throughout the formation of heterotopic bone in injured Achilles tendons, and the serum melatonin levels were increased after the initial injury. Double immunofluorescence showed that the MT2 melatonin receptor was notably expressed at the sites of injury. Micro-CT showed the enhancement of heterotopic bone volume and calcified areas in rats treated with melatonin. Additionally, our data showed that melatonin induced EndMT in primary rat aortic endothelial cells (RAOECs), which acquired traits including migratory function, invasive function and EndMT and MSC marker gene and protein expression. Furthermore, our data exhibited that melatonin promoted the osteogenic differentiation of RAOECs undergoing EndMT in vitro. Importantly, inhibition of the melatonin-MT2 pathway by using the MT2 selective inhibitor 4-P-PDOT inhibited melatonin-induced EndMT and osteogenesis both in vivo and in vitro. In conclusion, these findings demonstrated that melatonin promoted HO through the regulation of EndMT in injured Achilles tendons in rats, and these findings might provide additional directions for the management of HO.

scholarly journals Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

2020 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Jinpeng Li ◽  
Yuta Takagaki ◽  
Munehiro Kitada ◽  
Julie E. Goodwin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Renal Tubular ◽  
Defective Metabolism

Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain-of-function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis; while its loss-of-function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked-activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-dependent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial cell SIRT3 is a fundamental regulator of defective metabolism-regulating health and disease processes in the kidney.

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