Integrin, Exosome and Kidney Disease

Shen, Anran; Zhong, Xin; Tang, Tao-Tao; Wang, Cui; Jing, Jing; Liu, Bi‐Cheng; Lv, Lin‐Li

doi:10.3389/fphys.2020.627800

Cited by 20 publications

(16 citation statements)

References 71 publications

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“…Most integrins exhibit an ability to bind a wide range of ligands [ 29 ]. Many studies have unequivocally demonstrated that integrins can bind with noncanonical molecules to orchestrate downstream signaling pathways [ 30 ]. For example, some integrins bind and activate TGF-β to elicit Smad2/3 signaling, which promotes interstitial fibrosis and suppress TEC proliferation [ 31 ].…”

Section: Supar and Integrins: When And Wherementioning

confidence: 99%

suPAR: An Inflammatory Mediator for Kidneys

Sudhini¹,

Wei²,

Reiser³

2022

Kidney Dis

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Background: Inflammation is a common feature of many kidney diseases. The implicated inflammatory mediators and their underlying molecular mechanisms however are often not clear. Summary: suPAR is the soluble form of urokinase-type plasminogen activator receptor (uPAR), associated with inflammation and immune activation. It has evolved into a unique circulating kidney disease factor over the last 10 years. In particular, suPAR has multiple looks due to enzymatic cleavage and alternative transcriptional splicing of the uPAR gene. Most recently, suPAR has emerged as a systemic mediator for COVID-19 infection, associated with lung as well as kidney dysfunction. Like membrane-bound uPAR, suPAR could interact with integrins (e.g., αvβ3 integrin) on podocytes, providing the molecular basis for some glomerular kidney diseases. In addition, there have been numerous studies suggesting that suPAR connects acute kidney injury to chronic kidney disease as a special kidney risk factor. Moreover, the implication of circulating suPAR levels in kidney transplantation and plasmapheresis not only indicates its relevance in monitoring for recurrence but also implies suPAR as a possible therapeutic target. In fact, the therapeutic concept of manipulating suPAR function has been evidenced in several kidney disease experimental models. Key Messages: The last 10 years of research has established suPAR as a unique inflammatory mediator for kidneys. While open questions remain and deserve additional studies, modulating suPAR function may represent a promising novel therapeutic strategy for kidney disease.

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Section: Supar and Integrins: When And Wherementioning

confidence: 99%

suPAR: An Inflammatory Mediator for Kidneys

Sudhini¹,

Wei²,

Reiser³

2022

Kidney Dis

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“…MiRNAs are small noncoding RNAs that play a negative regulatory role at the posttranscriptional gene level and have been proven to be involved in the development of renal fibrosis caused by hydronephrosis 15 , 16 . On the other hand, exosomes are also closely related to renal fibrosis caused by hydronephrosis, diabetes or ischemia reperfusion injury 17 , 18 . However, most of these studies merely reflect the diagnostic and therapeutic value of exosomes 19 - 20 .…”

Section: Introductionmentioning

confidence: 99%

Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys

Zhao

et al. 2021

Theranostics

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Rationale: Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. Methods: We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed in vitro and in vivo by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Results: Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis in vitro and in vivo . In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation in vitro , and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes in vivo through the PTEN/Akt pathway. Conclusion: Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.

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“…Exosomes are an important and universal form of intercellular communication, and can mediate communication between organs (35). In addition, exosomes can be used as therapeutic carriers and serve as biomarkers to diagnose several diseases in a non-invasive manner (36).…”

Section: Discussionmentioning

confidence: 99%

Exosome‑encapsulated miR‑26a attenuates aldosterone‑induced tubulointerstitial fibrosis by inhibiting the CTGF/SMAD3 signaling pathway

Zheng

Zhao

et al. 2022

Int J Mol Med

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Renal tubulointerstitial fibrosis (TIF) is a hallmark in the continuous progression of chronic kidney disease (CKD), in which excessive activation of the renin-angiotensinaldosterone system serves a crucial role. Currently, there are no targeted therapies for the progression of TIF. microRNA (miR)-26a may be an ideal anti-fibrosis candidate molecule; however, the effect of miR-26 on aldosterone (ALD)-induced TIF remains unclear. This study aimed to elucidate the role of miR-26a in ALD-induced TIF. In the present study, we hypothesized that delivery of miR-26a by exosomes could attenuate ALD-induced TIF. miR-26a expression was downregulated in the kidney of ALD-induced mice compared with the mice in the sham group. Exosome-encapsulated miR-26a (Exo-miR-26a) was manufactured and injected into ALD-treated mice through the tail vein. In vivo experiments showed that Exo-miR-26a alleviated the downregulated miR-26a expression in the kidney, tubular injury and ALD-induced TIF, which was determined using Masson's trichrome staining and assessment of lipocalin 2, α-smooth muscle actin, collagen I and fibronectin expression. Moreover, in vitro experiments revealed that Exo-miR-26a inhibited epithelial-mesenchymal transition and extracellular matrix deposition in mouse tubular epithelial cells. Mechanistically, overexpressing miR-26a led to decreased expression levels of connective tissue growth factor by directly binding to its 3'-UTR and inhibiting the activation of SMAD3. These findings demonstrated that the exosomal delivery of miR-26a may alleviate ALD-induced TIF, which may provide new insights into the treatment of CKD.

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Integrin, Exosome and Kidney Disease

Cited by 20 publications

References 71 publications

suPAR: An Inflammatory Mediator for Kidneys

suPAR: An Inflammatory Mediator for Kidneys

Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys

Exosome‑encapsulated miR‑26a attenuates aldosterone‑induced tubulointerstitial fibrosis by inhibiting the CTGF/SMAD3 signaling pathway

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