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

Qi, Ruochen; Yang, Cheng

doi:10.1038/s41419-018-1157-x

Cited by 184 publications

(168 citation statements)

References 122 publications

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“…With the progression of disease, the massive collagen deposition in the interstitial area could invade nearby nephron, the basic structural and functional unit of the kidney, and spread quickly. In humans with a variety of nephropathies and experimental CKD models, it is often seen that tubular cells may undergo cell injury in different ways with the secretion of fibrosis‐related molecules, especially in the late stage of disease . Large numbers of reports show that tubular epithelial cells could transit into mesenchymal, dedifferentiated and senescent phenotypes to secret matrix‐synthesizing molecules such as TGF‐β1 and proinflammatory cytokines such as IL‐6 .…”

Section: Discussionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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Section: Discussionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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“…Therefore, our studies provide evidence for the notion that MMP-7 mediates tubuloglomerular communication in diseased kidneys. Previous studies have shown that there is a complex crosstalk between renal tubular cells and interstitial fibroblasts, leading to the development of fibrosis (27)(28)(29). It has also been appreciated that primary glomerular injuries can lead to tubular injury, which is evidenced by the development of tubular atrophy and interstitial fibrosis in a variety of primary glomerular disorders (3).…”

Section: Discussionmentioning

confidence: 99%

Tubular injury triggers podocyte dysfunction by β-catenin–driven release of MMP-7

Tan¹,

Li²,

Rush³

et al. 2019

JCI Insight

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While highly active during development, Wnt/β-catenin signaling becomes quiescent in adult kidneys and reactivates during kidney injury (7-10). Activation of this signaling leads to a fibrotic response and promotes the progression of CKD via the upregulation of profibrotic mediators, such as fibronectin, the renin-angiotensin system, plasminogen activator inhibitor-1, and [11][12][13]. Induction of MMP-7 by Wnt/β-catenin is particularly interesting, because it is the most robust β-catenin downstream target, and its expression primarily occurs in renal tubules (14-16). As a secreted protein that can be detected in the urine, MMP-7 is an effective noninvasive urinary biomarker for activation of Wnt/β-catenin after kidney injury (16,17).In the current study, we evaluated kidney injury after chronic infusion of angiotensin II (Ang II) using conditional knockout mice with tubule-specific ablation of β-catenin (18). Interestingly, although the genetic mutation was restricted to renal tubules, we found that these mice had significant protection against glomerular injury and proteinuria, accompanied by a reduced MMP-7 expression. These results were replicated in an Adriamycin-induced proteinuria model. We further demonstrate that MMP-7 could degrade the slit diaphragm protein nephrin and impaired integrity of the glomerular filtration barrier. In vivo exposure of mice to elevated MMP-7 levels was sufficient to cause proteinuria, and global ablation of MMP-7 protected mice from Ang II-induced glomerular injury. Our findings illustrate that tubular injury promotes glomerular damage by β-catenin-driven release of MMP-7.

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“…Injury-induced EMT eventually leads to fibrosis [40]. Preventing the initiation of EMT results in the reduction of myofibroblast recruitment and extracellular matrix deposition, and hence preserves functional TECs and improves organ function [13].…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor-mediated CaMKII/ERK Activation Contributes to Renal Fibrosis

Zhou

Liu

Guo

et al. 2020

Preprint

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Background: Renal fibrosis (RF) results in renal function impairment and eventually kidney failure. We found that N-methyl-D-aspartate receptor (NMDAR) played an important role during RF. However, its mechanism of action is yet to be deciphered. Methods: Acute RF was induced in mice by unilateral ureteral obstruction (UUO). NR1, which is the functional subunit of NMDAR, was downregulated using lentiviral vector-mediated shRNA interference. Histological changes were observed by Masson’s trichrome staining. Expression of NR1, fibrotic and EMT markers were measured by immunohistochemistry and western blot analysis. HK-2 cells were incubated with TGF-β, and NMDAR antagonist MK-801 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) antagonist KN-93 administration were further included in this study for pathway determination. Expression of NR1, total and phosphorylated CaMKII, total and phosphorylated ERK were measured using western blot and immunofluorescent assays. Chronic renal fibrosis was introduced by sublethal ischemia-reperfusion injury in mice, and oral NMDAR inhibitor dextromethorphan (DXM) administration was performed. Results: NR1 expressions were upregulated in both obstructed kidneys and TGF-β treated HK-2 cells. NR1 knockdown, DXM, MK801, and KN93 reduced the fibrotic morphology in vivo and in vitro respectively, and companied with the downregulated ERK activation, while KN93 administration had no effect on NR1 and CaMKII levels. Conclusions: NMDAR participates in both acute and chronic renal fibrogenesis via CaMKII/ERK activation, and is a potential therapeutic target for renal fibrosis.

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

Cited by 184 publications

References 122 publications

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Tubular injury triggers podocyte dysfunction by β-catenin–driven release of MMP-7

NMDA Receptor-mediated CaMKII/ERK Activation Contributes to Renal Fibrosis

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