Transforming growth factor β (TGFβ) and related molecules in chronic kidney disease (CKD)

Huynh, Pacific; Chai, Zhonglin

doi:10.1042/cs20180438

Cited by 41 publications

(37 citation statements)

References 365 publications

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“…TGF-β and its receptor are expressed ubiquitously by most cell types. As TGF-β pathway participates in regulating the expression of fibrotic genes such as collagens and fibronectin, increased level of TGF-β can lead to fibrosis both in vivo and vitro experiments [34–36]. In the presence of TGF-β, pericytes increased and underwent a morphological change through transition into α-SMA-positive myofibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Putative endothelial progenitor cells do not promote vascular repair but attenuate pericyte–myofibroblast transition in UUO-induced renal fibrosis

et al. 2019

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BackgroundPutative endothelial progenitor cells (pEPCs) have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases. However, their mechanistic effect on renal fibrosis, which is characterized by vascular regression and further rarefaction-related pathology, remains unknown.MethodsTo explore the effect and molecular mechanisms by which pEPCs act on unilateral ureteral obstruction (UUO)-induced renal fibrosis, we isolated pEPCs from murine bone marrow. In vivo, pEPCs (2 × 105 cells/day) and pEPC-MVs (microvesicles) were injected into UUO mice via the tail vein. In vitro, pEPCs were co-cultured with renal-derived pericytes. Pericyte-myofibroblast transition was evaluated using the myofibroblast marker α-smooth muscle actin (α-SMA) and pericyte marker platelet-derived growth factor receptor β (PDGFR-β).ResultsExogenous supply of bone marrow-derived pEPCs attenuated renal fibrosis by decreasing pericyte-myofibroblast transition without significant vascular repair in the UUO model. Our results indicated that pEPCs regulated pericytes and their transition into myofibroblasts via pEPC-MVs. Co-culture of pericytes with pEPCs in vitro suggested that pEPCs inhibit transforming growth factor-β (TGF-β)-induced pericyte–myofibroblast transition via a paracrine pathway.ConclusionpEPCs effectively attenuated UUO-induced renal fibrosis by inhibiting pericyte–myofibroblast transition via a paracrine pathway, without promoting vascular repair.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1201-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Putative endothelial progenitor cells do not promote vascular repair but attenuate pericyte–myofibroblast transition in UUO-induced renal fibrosis

et al. 2019

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“…In renal endothelial cells, TGF-β1 mediates renal fibrosis by inducing modifications characteristic of endothelial–mesenchymal transition (EndMT) [39,40], a phenomenon whereby endothelial cells begin to express the characteristics of mesenchymal cells, with the acquisition of mesenchymal markers like α-smooth muscle actin (αSMA) [9] and loss of endothelial markers like VE-cadherin and CD31 [9,40]. TGF-β was a promising therapeutic target in animal models of DKD [41]. However, results of TGF-β inhibition were disappointing in humans [42].…”

Section: Effect Of High Glucose and By-products On Renal Endothelimentioning

confidence: 99%

“…A therapeutic trial aiming to replenish glycocalyx through the ingestion of sulodexide (a mixture of glycosaminoglycans) in patients with type 2 diabetes failed to demonstrate a benefit compared to placebo on GFR decline or proteinuria [26,27]. In addition, whereas targeting TGF-β was promising in animals with DKD [41], TGFβ-1 inhibition by a monoclonal antibody failed to slow the progression of DKD in patients [42].…”

Section: Effect Of High Glucose and By-products On Renal Endothelimentioning

confidence: 99%

Endothelial Toxicity of High Glucose and its by-Products in Diabetic Kidney Disease

Dou

Jourde-Chiche

2019

Toxins

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Alterations of renal endothelial cells play a crucial role in the initiation and progression of diabetic kidney disease. High glucose per se, as well as glucose by-products, induce endothelial dysfunction in both large vessels and the microvasculature. Toxic glucose by-products include advanced glycation end products (AGEs), a group of modified proteins and/or lipids that become glycated after exposure to sugars, and glucose metabolites produced via the polyol pathway. These glucose-related endothelio-toxins notably induce an alteration of the glomerular filtration barrier by increasing the permeability of glomerular endothelial cells, altering endothelial glycocalyx, and finally, inducing endothelial cell apoptosis. The glomerular endothelial dysfunction results in albuminuria. In addition, high glucose and by-products impair the endothelial repair capacities by reducing the number and function of endothelial progenitor cells. In this review, we summarize the mechanisms of renal endothelial toxicity of high glucose/glucose by-products, which encompass changes in synthesis of growth factors like TGF-β and VEGF, induction of oxidative stress and inflammation, and reduction of NO bioavailability. We finally present potential therapies to reduce endothelial dysfunction in diabetic kidney disease.

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“…It is believed that activated myofibroblasts are the main culprit in the deposition of ECM. Transforming growth factor (TGF)-β, abundantly expressed in fibrotic diseases, is currently considered to be a key mediator of these disorders (Ding et al, 2014; Sosulski et al, 2015; Musso et al, 2016; Cianfarani et al, 2018; Russo et al, 2019; Huynh and Chai, 2019). A growing body of research suggests that TGF-β1 is the most significant regulatory mediator of myofibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Hydroxycamptothecin Inhibits Peritendinous Adhesion via the Endoplasmic Reticulum Stress-Dependent Apoptosis

et al. 2019

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Traumatic peritendinous fibrosis is a worldwide clinical problem resulting in severe limb disability. Hydroxycamptothecin (HCPT) is an anti-neoplastic drug widely exploited in clinical practice. It has shown potential of anti-fibrosis in recent years. We previously demonstrated that HCPT inhibited the characterization of fibrosis in vitro. However, it is still unclear whether it ameliorates peritendinous adhesion in an in vivo animal tendon injury model. The underlying mechanism is also worth investigating. The present study aims to determine whether HCPT inhibits tendon adhesion and to explore the underlying mechanisms. In a rat tendon injury model, we observed that topical application of HCPT significantly attenuated peritendinous adhesion as revealed by the results of macroscopic observation, biomechanical, histological, immunohistochemical evaluation, western blot, and quantitative PCR (q-PCR) analyses. Furthermore, western blot and q-PCR analyses revealed that this phenomenon is correlated with HCPT activation of endoplasmic reticulum (ER) stress. In addition, in vitro studies show that HCPT significantly inhibits fibroblast proliferation and induces apoptosis by reducing the expression of extracellular matrix (ECM) proteins COL3A1 and α-smooth muscle actin (α-SMA). Finally, we employed small interfering RNA (siRNA) to target inositol requiring kinase 1 (IRE1) and activated transcription factor 6 (ATF-6) to verify that the effect of inhibitory fibrosis of HCPT disappears after knockdown of ATF-6 and IRE1, thereby suggesting that an anti-fibrotic effect of HCPT is mediated by the ER-dependent apoptotic pathway. In conclusion, our results indicate that HCPT inhibits peritendinous fibrosis through the ER-dependent apoptotic pathway and might serve as a potential solution to prevent traumatic peritendinous adhesion.

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Transforming growth factor β (TGFβ) and related molecules in chronic kidney disease (CKD)

Cited by 41 publications

References 365 publications

Putative endothelial progenitor cells do not promote vascular repair but attenuate pericyte–myofibroblast transition in UUO-induced renal fibrosis

Putative endothelial progenitor cells do not promote vascular repair but attenuate pericyte–myofibroblast transition in UUO-induced renal fibrosis

Endothelial Toxicity of High Glucose and its by-Products in Diabetic Kidney Disease

Hydroxycamptothecin Inhibits Peritendinous Adhesion via the Endoplasmic Reticulum Stress-Dependent Apoptosis

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