Transforming growth factor‐β1 stimulates hedgehog signaling to promote epithelial–mesenchymal transition after kidney injury

Lu, Hong; Chen, Bicheng; Hong, Weilong; Liang, Yong; Bai, Yongheng

doi:10.1111/febs.13842

Cited by 26 publications

(17 citation statements)

References 47 publications

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“…In UUO kidneys, upregulated expression levels of molecules involved in the activation of hedgehog signaling are primarily located around the tubules, which are rich in tubular epithelial cells (17). However, whether activation of hedgehog signaling is responsible for the proliferation of epithelial cells remains unknown.…”

Section: Resultsmentioning

confidence: 99%

Anti-fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway

Bai

Hong

et al. 2017

Molecular Medicine Reports

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Sedum sarmentosum Bunge (SSBE) is a perennial plant widely distributed in Asian countries, and its extract is traditionally used for the treatment of certain inflammatory diseases. Our previous studies demonstrated that SSBE has marked renal anti-fibrotic effects. However, the underlying molecular mechanisms remain to be fully elucidated. The present study identified that SSBE exerts its inhibitory effect on the myofibroblast phenotype and renal fibrosis via the hedgehog signaling pathway in vivo and in vitro. In rats with unilateral ureteral obstruction (UUO), SSBE administration reduced kidney injury and alleviated interstitial fibrosis by decreasing the levels of transforming growth factor (TGF)-β1 and its receptor, and inhibiting excessive accumulation of extracellular matrix (ECM) components, including type I and III collagens. In addition, SSBE suppressed the expression of proliferating cell nuclear antigen, and this anti-proliferative activity was associated with downregulation of hedgehog signaling activity in SSBE-treated UUO kidneys. In cultured renal tubular epithelial cells (RTECs), recombinant TGF-β1 activated hedgehog signaling, and resulted in induction of the myofibroblast phenotype. SSBE treatment inhibited the activation of hedgehog signaling and partially reversed the fibrotic phenotype in TGF-β1-treated RTECs. Similarly, aristolochic acid-mediated upregulated activity of hedgehog signaling was reduced by SSBE treatment, and thereby led to the abolishment of excessive ECM accumulation. Therefore, these findings suggested that SSBE attenuates the myofibroblast phenotype and renal fibrosis via suppressing the hedgehog signaling pathway, and may facilitate the development of treatments for kidney fibrosis.

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Section: Resultsmentioning

confidence: 99%

Anti-fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway

Bai

Hong

et al. 2017

Molecular Medicine Reports

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“…Tubular epithelial cells (TECs) serve important roles in maintaining renal function and the progression of TIF (2). Kidney injury may lead to the phenotypic transformation of TECs (3), which is similar to the process of epithelial mesenchymal transition (EMT). Under such conditions, TECs acquire some properties of fibroblasts, producing excessive extracellular matrix (ECM) and related proteins, including collagen and fibronectin, leading to fibrosis of the kidney cells and eventual nephropathy (4,5).…”

Section: Introductionmentioning

confidence: 99%

Quercetin is able to alleviate TGF‑β‑induced fibrosis in renal tubular epithelial cells by suppressing miR‑21

Cao

Jianying

et al. 2018

Exp Ther Med

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Patients with chronic kidney disease (CKD) are characterized by a gradual loss of kidney function over time. A number of studies have indicated that tubule interstitial fibrosis (TIF) is associated with the occurrence and development of CKD. The aim of the present study was to investigate the effect of quercetin treatment on the fibrosis of renal tubular epithelial cells and to determine whether the anti-fibrotic effects of quercetin are achieved via microRNA (miR)-21. Human tubular epithelial HK-2 cells were cultured with transforming growth factor (TGF)-β to induce fibrosis and the expression of fibrotic markers collagen I, fibronectin, α-smooth muscle actin (SMA) and epithelial-cadherin were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cells were treated with 7.5, 15 or 30 mg/ml quercetin, following which fibrosis and miR-21 expression were evaluated. Quercetin-treated cells were transfected with miR-21 mimics and the expression of fibrotic markers was examined using RT-qPCR. Finally, the expression of fibrosis-associated miR-21 target genes, phosphatase and tensin homolog (PTEN) and TIMP Metallopeptidase Inhibitor 3 (TIMP3), was measured in cells treated with quercetin with or without miR-21 mimics using RT-qPCR, western blotting and immunocytochemistry. The results revealed that TGF-β treatment induced a significant increase in the expression of fibrotic markers in HK-2 cells, while quercetin treatment partially inhibited the fibrosis of HK-2 cells. Furthermore, quercetin treatment significantly inhibited TGF-β-induced miR-21 upregulation and transfection with miR-21 mimics reversed the anti-fibrotic effects of quercetin. Quercetin treatment markedly upregulated PTEN and TIMP3 expression, whereas transfection with miR-21 mimics reversed this effect. The results of the present study suggest that quercetin is able to alleviate TGF-β-induced fibrosis in HK-2 cells via suppressing the miR-21 and upregulating PTEN and TIMP3. Quercetin may have potential as an anti-fibrotic treatment for patients with renal fibrosis.

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“…However, the underlying mechanism remains unknown. A number of crucial signaling molecules, including proteins in the hedgehog family ( 31 ), WNT family ( 32 ), interleukin family ( 33 ) and TGF-β super family ( 34 ), may induce or contribute to EMT. In hepatic fibrosis, the hedgehog signaling pathway is activated by the binding of its ligands, including Shh, to its membrane receptor patched 1 (Ptch1).…”

Section: Discussionmentioning

confidence: 99%

Hesperetin alleviates renal interstitial fibrosis by inhibiting tubular epithelial-mesenchymal transition in vivo and in vitro

Wang¹,

Shi

et al. 2017

Experimental and Therapeutic Medicine

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Hesperetin (HES) is a flavonoid that has been reported to exert protective effects against cardiac remodeling, lung fibrosis and hepatic fibrosis. However, reports on the effects and potential mechanisms of HES in renal fibrosis are limited. In the present study, a unilateral ureteric obstruction (UUO) mouse model and a transforming growth factor (TGF)-β1-activated normal rat kidney (NRK)-52E cell model were established. HES was subsequently administered to these models to evaluate its anti-fibrotic effects and potential underlying mechanisms of action. The results demonstrated that HES reduced obstruction-induced renal injury and deposition of the extracellular matrix components collagen-I and fibronectin in UUO mouse kidneys (P<0.05). Furthermore, HES treatment significantly suppressed EMT, as evidenced by decreased expression of α-smooth muscle actin and E-cadherin, (P<0.05). Additionally, HES inhibited the hedgehog signaling pathway in UUO mice and TGF-β1-treated NRK-52E cells. The present findings indicate that HES treatment may inhibit EMT and renal fibrosis in vivo and in vitro by antagonizing the hedgehog signaling pathway.

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Transforming growth factor‐β1 stimulates hedgehog signaling to promote epithelial–mesenchymal transition after kidney injury

Cited by 26 publications

References 47 publications

Anti-fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway

Anti-fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway

Quercetin is able to alleviate TGF‑β‑induced fibrosis in renal tubular epithelial cells by suppressing miR‑21

Hesperetin alleviates renal interstitial fibrosis by inhibiting tubular epithelial-mesenchymal transition in vivo and in vitro

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