New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis

Sheng, Lili; Zhuang, Songlin

doi:10.3389/fphys.2020.569322

Cited by 141 publications

(95 citation statements)

References 112 publications

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“…Epithelial-mesenchymal transition (EMT) of tubular epithelial cells has long been considered a pro-fibrotic mechanism. Recent evidence indicates that renal epithelial cells undergo a partial-EMT where epithelial cells develop fibroblastlike characteristics, without a complete conversion to fibroblasts [28]. IS induced an EMTlike process in vitro and in vivo through activation of the renin-angiotensin system (RAS), further contributing to renal fibrosis [29].…”

Section: Indoxyl Sulfatementioning

confidence: 99%

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Lim

Sidor

Tonial

et al. 2021

Toxins

119

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Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

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Section: Indoxyl Sulfatementioning

confidence: 99%

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Lim

Sidor

Tonial

et al. 2021

Toxins

119

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“…The onset of G1 initiates degradation of Ki67 (Miller et al, 2018). These cellular mechanisms have been considered to be part of the kidney's adaptive repair process, which ultimately results in fibrosis (Nadasdy et al, 1994;Sheng and Zhuang, 2020).…”

Section: Discussionmentioning

confidence: 99%

ATXN10 is required for embryonic heart development and maintenance of epithelial cell phenotypes in the adult kidney and pancreas

Bentley-Ford

et al. 2021

Preprint

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Atxn10 is a gene known for its role in cytokinesis during the cell cycle and is associated with Spinocerebellar Ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes Nephronophthisis (NPHP) and Joubert Syndrome (JBTS), which are caused by disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt Atxn10 systemically, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial to mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotoype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively this study identifies ATXN10 as an essential protein for survival.

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“…In fact, probably because of the variety of experimental models used, there is a certain amount of confusion in the literature. For a broad discussion on this matter we refer you to recent reviews ( Cruz-Solbes and Youker, 2017 ; Sheng and Zhuang, 2020 ) ( Figure 5 ).…”

Section: Organ Fibrosis Emt and Possible Anti-emt Therapeutic Stratementioning

confidence: 99%

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

Gregorio

Robuffo

Spalletta³

et al. 2020

Front. Cell Dev. Biol.

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Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-β) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-β in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.

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New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis

Cited by 141 publications

References 112 publications

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

ATXN10 is required for embryonic heart development and maintenance of epithelial cell phenotypes in the adult kidney and pancreas

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

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