Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

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Abstract

Renal fibrosis, especially tubulointerstitial fibrosis, is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For a long time, interests in renal fibrosis have been concentrated on fibroblasts and myofibroblasts. However, in recent years, growing numbers of studies have focused on the role of tubular epithelial cells (TECs). TECs, rather than a victim or bystander, are probably a neglected mediator in renal fibrosis, responding to a variety of injuries. The maladaptive repair mechanisms of TECs may be the key point in this process. In this review, we will focus on the role of TECs in tubulointerstitial fibrosis. We will follow the fate of a tubular cell and depict the intracellular changes after injury. We will then discuss how the repair mechanism of tubular cells becomes maladaptive, and we will finally discuss the intercellular crosstalk in the interstitium that ultimately proceeds tubulointerstitial fibrosis.

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Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.

David A Ferenbach, Joseph V. Bonventre (2015)

Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.

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Renal tubule injury: a driving force toward chronic kidney disease.

Lin-Li Lv, Tao‐Tao Tang, Bi-Cheng Liu … (2018)

Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease.

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TGF-β/Smad signaling in renal fibrosis

Xiao-ming Meng, Patrick Ming-Kuen Tang, Jun-Jun Li … (2015)

TGF-β (transforming growth factor-β) is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF-β signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix), and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases (CKD). Taken together, TGF-β/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.

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Author and article information

Contributors

Cheng Yang: +86 21 64041990 , esuperyc@163.com , yang.cheng1@zs-hospital.sh.cn

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 13 November 2018

Publication date PMC-release: 13 November 2018

Publication date Collection: November 2018

Volume: 9

Issue: 11

Electronic Location Identifier: 1126

Affiliations

[1 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Urology, Zhongshan Hospital, , Fudan University, ; 200032 Shanghai, P. R. China

[2 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Shanghai Medical College, , Fudan University, ; 200032 Shanghai, P.R. China

[3 ]ISNI 0000 0004 1755 3939, GRID grid.413087.9, Shanghai Key Laboratory of Organ Transplantation, ; 200032 Shanghai, P. R. China

Article

Publisher ID: 1157

DOI: 10.1038/s41419-018-1157-x

PMC ID: 6233178

PubMed ID: 30425237

SO-VID: bf566448-8c63-42da-a9b4-71b9be00e758

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 10 August 2018

Date revision received : 6 October 2018

Date accepted : 18 October 2018

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81400752

Award ID: 81770746

Award Recipient : Cheng Yang

Funded by: the National Key R&D Program of China (2018YFA0107502 to CY),the Medical and Health Talents Training Plan for the Excellent Youth of Shanghai Municipal(2018YQ50 to CY)

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Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

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Most cited references 104

Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.

Renal tubule injury: a driving force toward chronic kidney disease.

TGF-β/Smad signaling in renal fibrosis

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