Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector

Xu, Jing; Li, Pei-Xue; Wu, Jun; Gao, Yijun; Yin, Meng‐Xin; Lin, Ye; Yang, Ming; Chen, Dongping; Sun, Haipeng; Liu, Zeng-Bo; Gu, Xiangchen; Huang, Hongling; Fu, Lili; Hu, Huimin; He, Liangliang; Wu, Wenqing; Fei, Zhaoliang; Ji, Hongbin; Zhang, Lei; Mei, Changlin

doi:10.1042/cs20150385

Cited by 61 publications

(56 citation statements)

References 40 publications

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“…In kidney tubular epithelial cells, YAP overexpression induced cell proliferation and YAP/TAZ activation promoted EMT-like processes. 56,57 Our study also showed that YAP/TAZ overexpression after obstructive injury and epithelial dedifferentiation. However, synthetic TGF-β1/Smad ODN administration suppressed the expression of YAP/TAZ.…”

Section: Discussionsupporting

confidence: 61%

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Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Gwon

Kim

et al. 2019

FASEB j.

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Kidney fibrosis is a common process of various kidney diseases leading to end-stage renal failure irrespective of etiology. Myofibroblasts are crucial mediators in kidney fibrosis through production of extracellular matrix (ECM), but their origin has not been clearly identified. Many study proposed that epithelial and endothelial cells become myofibroblasts by epithelial dedifferentiation and endothelial-mesenchymal transition (EndoMT). TGF-β1/Smad signaling plays a crucial role in partly epithelial-mensencymal transition (EMT) and EndoMT. Thus, we designed the TGF-β1/ Smad oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequence for Smad transcription factor and TGF-β1 mRNA. Therefore, this study investigated the anti-fibrotic effect of synthetic TGF-β1/Smad ODN on UUO-induced kidney fibrosis in vivo model and TGF-β1-induced in vitro model.To examine the effect of TGF-β1/Smad ODN, we performed various experiments to evaluate kidney fibrosis. The results showed that UUO induced inflammation, ECM accumulation, epithelial dedifferentiation and EndoMT processes, and tubular atrophy. However, synthetic TGF-β1/Smad ODN significantly suppressed UUOinduced fibrosis. Furthermore, synthetic ODN attenuated TGF-β1-induced epithelial dedifferentiation and EndoMT program via blocking TGF-β1/Smad signaling. In conclusion, this study demonstrated that administration of synthetic TGF-β1/Smad ODN attenuates kidney fibrosis, epithelial dedifferentiation, and EndoMT processes.The findings propose the possibility of synthetic ODN as a new effective therapeutic tool for kidney fibrosis. K E Y W O R D SEndoMT, epithelial dedifferentiation, kidney fibrosis, TGF-β1/Smad oligodeoxynucleotide, UUO 334 | GWON et al. | MATERIALS AND METHODS | Synthesis of oligodeoxynucleotidesTarget site of TGF-β1 was selected using S-Fold program. Synthetic ODNs were synthesized on Macrogen (Seoul, Korea). TGF-β1/Smad ODN and scrambled (Scr) ODN 340 | GWON et al. F I G U R E 3 TGF-β1/Smad ODN attenuated kidney fibrosis and ECM accumulation in UUO-injured mice. A, Pathological stain withhematoxylin and eosin (H&E) and B, Masson's trichrome performed using kidney sections. Trichrome stain showed that TGF-β1/Smad ODN attenuated interstitial fibrosis. C, The quantitative analysis of blue-stained collagen in trichrome staining (n = 3). D, Collagen Ⅰ was detected by RT-PCR. This result demonstrated the effect of synthetic ODN on ECM accumulation. The graphs summarize the analysis of the Collagen Ⅰ mRNA expressions (n = 4). E, Immunohistochemistry stain showed that the expression of fibronectin was inhibited by TGF-β1/Smad ODN administration in UUO-injured mice. F, The quantitative graph of fibronectin expression. G, Representative Western blot data revealed that TGF-β1/Smad ODN diminished expression of fibronectin. β-actin was used to confirm equal volume protein sample loading (n = 3). Scale bar = 50 μm; +: treated; −: un-treated; *P < .05 compared to the normal control group; †P < .05 compared to the UUO group

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Section: Discussionsupporting

confidence: 61%

“…56,57 Our study also showed that YAP/TAZ overexpression after obstructive injury and epithelial dedifferentiation. In kidney tubular epithelial cells, YAP overexpression induced cell proliferation and YAP/TAZ activation promoted EMT-like processes.…”

Section: F I G U R Esupporting

confidence: 61%

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Gwon

Kim

et al. 2019

FASEB j.

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“…Loss of Sav1 is thought to result in an accumulation of Yap in the nucleus, where it binds to other transcription factors, such as the TEAD family of transcription factors, to activate expression of target genes (56,57). Previously published work suggested that Yap also plays a role in fibrosis (27,28,58,59). We assessed Yap levels in KS mice compared to those in age-matched controls and saw progressive increases in Yap accumulation at 6 weeks and Ͼ20 weeks post-tamoxifen treatment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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“…Paraffin-fixed kidney sections were cut into 3 lm sections and stained with haematoxylin and eosin (H&E) for histological assessment. The transverse tubular diameters were calculated as previously described [21]. Masson Trichrome and Sirus Red staining were both performed to assess the extent of fibrosis.…”

Section: Kidney Histology and Immunohistochemistry Evaluationmentioning

confidence: 99%

Antithrombin III prevents progression of chronic kidney disease following experimental ischaemic‐reperfusion injury

Yin

Wang

Kong

et al. 2017

J Cellular Molecular Medi

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Acute kidney disease (AKI) leads to increased risk of progression to chronic kidney disease (CKD). Antithrombin III (ATIII) is a potent anticoagulant with anti‐inflammatory properties, and we previously reported that insufficiencies of ATIII exacerbated renal ischaemia‐reperfusion injury (IRI) in rats. In this study, we examined the characteristic of AKI‐CKD transition in rats with two distinct AKI models. Based on our observation, left IRI plus right nephrectomy (NX‐IRI) was used to determine whether ATIII had therapeutic effects in preventing CKD progression after AKI. It was observed that NX‐IRI resulted in significant functional and histological damage at 5 weeks after NX‐IRI compared with sham rats, which was mitigated by ATIII administration. Besides, we noticed that ATIII administration significantly reduced NX‐IRI‐induced interstitial fibrosis. Consistently, renal expression of collagen‐1, α‐smooth muscle actin and fibronectin were substantial diminished in ATIII‐administered rats compared with un‐treated NX‐IRI rats. Furthermore, the beneficial effects of ATIII were accompanied with decreased M1‐like macrophage recruitment and down‐regulation of M1‐like macrophage‐dependent pro‐inflammatory cytokines such as tumour necrosis factor α, inducible nitric oxide synthase and interleukin‐1β, indicating that ATIII prevented AKI‐CKD transition via inhibiting inflammation. Overall, ATIII shows potential as a therapeutic strategy for the prevention of CKD progression after AKI.

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Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector

Abstract: The Hippo pathway plays a stage-specific role in regeneration and fibrogenesis after ischaemia/reperfusion-induced acute kidney injury. The proper modulation of this pathway might be the key point of transition from acute kidney injury to chronic kidney disease.

Cited by 61 publications

References 40 publications

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Antithrombin III prevents progression of chronic kidney disease following experimental ischaemic‐reperfusion injury

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