Inhibition of STAT3 activation mediated by toll‐like receptor 4 attenuates angiotensin II‐induced renal fibrosis and dysfunction

Xu, Zheng; Zou, Chunpeng; Wang, Yu; Xu, Sujing; Huang, Lan; Khan, Zia A.; Wang, Jingying; Liang, Guang; Wang, Yi

doi:10.1111/bph.14686

Cited by 19 publications

(10 citation statements)

References 67 publications

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“…Many studies have shown that inhibition of the STAT3 signaling pathway reduces renal inflammatory response and renal interstitial fibrosis. 43 , 44 , 45 Our in vivo experiments demonstrated that although high-intensity exercise had no effect on renal EMT, it significantly activated STAT3. In vitro experiments then confirmed that irisin upregulates p-STAT3 and activates the STAT3 pathway.…”

Section: Discussionmentioning

confidence: 69%

Aerobic exercise inhibits renal EMT by promoting irisin expression in SHR

Luo¹,

Luo²,

Xue³

et al. 2023

iScience

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Section: Discussionmentioning

confidence: 69%

Aerobic exercise inhibits renal EMT by promoting irisin expression in SHR

Luo¹,

Luo²,

Xue³

et al. 2023

iScience

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“…We have recently shown that Ang II activates STAT3 in renal epithelial cells to increase the expression of fibrotic factors COL-4 and TGF-β1. 12 Our present study demonstrates that a possible mechanism of increased STAT3 activity may be FGFR1. We show that inhibiting FGFR1 by ADZ4547 or reducing its expression supresses Ang II–induced STAT3 Y705 phosphorylation and downstream fibrotic factor expression.…”

Section: Discussionmentioning

confidence: 50%

Ang II (Angiotensin II)–Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury

Luo

Chen

et al. 2022

Hypertension

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Background: Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. Methods: Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. Results: Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II–induced fibrogenic responses in epithelial cells. Mechanistically, Ang II–activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. Conclusions: Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.

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“…Additionally, the roles of IL-6 were reported in several kidney diseases and targeting IL-6 could protect against renal fibrosis by suppressing STAT3 activation [ 34 , 35 ]. Some studies have found that STAT3 signaling can control the EMT of renal tubular epithelial cells during renal injury, and dysregulated STAT3 may lead to renal disease, including inflammation and fibrosis [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

PM2.5 Induces Early Epithelial Mesenchymal Transition in Human Proximal Tubular Epithelial Cells through Activation of IL-6/STAT3 Pathway

Lin

Wan

Liu

et al. 2021

IJMS

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Particulate matter exposure has been known as a potential risk for the global burden of disease, such as respiratory and cardiovascular diseases. Accumulating evidence suggests that PM2.5 (particulate matter with a diameter less than 2.5 μm) is associated with increased risk of kidney disease, but the mechanisms underlying the renal injury caused by PM2.5 remain to be elucidated. This study investigated the effects of PM2.5 on human proximal tubular epithelial (HK-2) cells by monolayer and 3D spheroid cultures and explored the potential mechanisms. The typical morphology of HK-2 cells showed epithelial–mesenchymal transition (EMT), resulting in reduced adhesion and enhanced migration after PM2.5 exposure, and was accompanied by decreased E-cadherin expression and increased vimentin and α-SMA expressions. Exposure to PM2.5 in the HK-2 cells could lead to an increase in interleukin-6 (IL-6) levels and cause the activation of signal transducer and activator of transcription 3 (STAT3), which is involved in EMT features of HK-2 cells. Furthermore, blocking IL-6/STAT3 signaling by an IL-6 neutralizing antibody or STAT3 inhibitor was sufficient to reverse PM2.5-induced EMT characteristics of the HK-2 cells. Our study suggests that PM2.5 could induce early renal tubule cell injury, contributing to EMT change, and the induction of IL-6/STAT3 pathway may play an important role in this process.

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Inhibition of STAT3 activation mediated by toll‐like receptor 4 attenuates angiotensin II‐induced renal fibrosis and dysfunction

Cited by 19 publications

References 67 publications

Aerobic exercise inhibits renal EMT by promoting irisin expression in SHR

Aerobic exercise inhibits renal EMT by promoting irisin expression in SHR

Ang II (Angiotensin II)–Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury

PM2.5 Induces Early Epithelial Mesenchymal Transition in Human Proximal Tubular Epithelial Cells through Activation of IL-6/STAT3 Pathway

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