Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang, Bin; Ding, Wei; Zhang, Minmin; Li, Hongmei; Gu, Yong

doi:10.1159/000369680

Cited by 43 publications

(31 citation statements)

References 30 publications

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“…In the tubulointersitium, tubular epithelial cells are the initial site of injury, and then interstitial fibroblasts are activated [9]. Tubular epithelial cells undergo EMT under many pathophysiological conditions [36]. This process promotes tubular epithelial cell transformation into profibrotic myofibroblasts that express the myofibroblast marker α-SMA [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD⁺-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

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“…In addition to producing various ECM proteins, epithelial cells undergo epithelial-mesenchymal transition (EMT) in the presence of certain inflammatory cytokines, thereby promoting the occurrence and development of fibrosis [9]. During EMT, epithelial cells acquire certain characteristics of the stromal cells around them, as seen by the loss of epithelial polarity and the acquisition of stromal features, including a stromal-like appearance, and vimentin, snail, and osteopontin expression [10, 11].…”

Section: Introductionmentioning

confidence: 99%

“…Vimentin and albumin expression levels also decreased significantly at the gene and protein levels [7]. In addition, Chen et al [9]. demonstrated that TGF-β1 induces EMT in human lung cancer A549 cells, as demonstrated by changes in mesenchymal morphology, increase in invasion and metastasis ability, up-regulation of the mesenchymal marker genes encoding vimentin and fibronectin, and down-regulation of the epithelial marker E-cadherin [15, 16].…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

Chen

Yang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Transforming growth factor-β1 (TGF-β1) plays a crucial role in chronic inflammation in various tissues, and is related to inflammation-caused organ fibrogenesis associated with the epithelial-mesenchymal transition (EMT) and the deposition of the extracellular matrix (ECM). However, the effect of TGF-β1 on bovine mammary epithelial cells (BMECs) with mastitis, and its mechanism, remain unknown. Methods: We analyzed the level of TGF-β1 in inflamed mammary tissues and cells using western blotting. BMECs were treated with TGF-β1, and EMT-related gene and protein expression changes were evaluated using quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescence. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor, and analyzed EMT-related protein expression by western blotting. In addition, we injected TGF-β1 into mice mammary glands to investigate whether it can cause mammary fibrosis in vivo. Results: The TGF-β1 level was up-regulated in mammary tissues with mastitis and in inducible inflammatory BMECs. TGF-β1 treatment activated the TGF/ Smad signaling pathway in BMECs during their transition to the EMT phenotype, as indicated by morphological changes from a cobblestone-like shape to a spindle-like one. TGF-β1 treatment also up-regulated the expression of α-smooth muscle actin, vimentin, and collagen I, albumin, and down-regulated the expression of E-cadherin both in mRNA level and protein level. Furthermore, TGF-β1 enhanced the gene expressions of MMP2, MMP7, and fibronectin in BMECs. TGF-β1 injection induced mice mammary infection and fibrosis. Conclusion: These findings suggested that aberrant up-regulation of TGF-β1 in bovine mastitic mammary glands might play an important role in bovine mammary fibrosis caused by unresolved inflammation.

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“…Without any appropriate intervention, it would gradually lead to the conversion of tubulointerstitial inflammation to TIF and worsen renal insufficiency. 3,29 The anti-inflammation property of ozone therapy has been made aware by some researchers. For instance, Alvarez realized ozone therapy could suppress inflammation state of rats suffering from LPS-induced endotoxic shock.…”

Section: Discussionmentioning

confidence: 99%

Ozone therapy ameliorates tubulointerstitial inflammation by regulating TLR4 in adenine-induced CKD rats

Chen

Liu

et al. 2016

Renal Failure

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Tubulointerstitium inflammation is a common pathway aggravating chronic kidney disease (CKD) progression and the mechanism is partly associated with excessive activation of toll-like receptor 4 (TLR4) in tubulointerstitium. Ozone therapy is demonstrated to alleviate inflammation in some experiments. The aim of this study is to examine whether ozone therapy could ameliorate chronic tubulointerstitium inflammation by suppressing TLR4 in adenine-induced CKD rats. SpragueDawley rats were fed with 0.75% adenine-containing diet to induce CKD and tubulointerstitium inflammation injury. Ozone therapy (1.1 mg/kg) was simultaneously administrated by rectal insufflations (i.r.). After 4 weeks, serum and kidney samples were collected for detection. Renal function and systemic electrolyte were detected. Renal pathological changes were assessed by hematoxylin-eosin (H&E) staining and Masson trichrome (MT) staining. Immunohistochemistry, Western blot and Real-time PCR were applied to evaluate tubulointerstitium inflammation as well as the expression of TLR4 and phosphorylated nuclear factor kappa B P65 (p-NF-kB P65) in rats. The results showed ozone therapy improved serious renal insufficiency, systemic electrolyte disorder and tubulointerstitium morphology damages in adenine-induced CKD rats. In addition, ozone therapy suppressed excessive activation of TLR4 and p-NF-kB P65 in the tubulointerstitium of adenine-induced CKD rats, accompanied by the reduction of inflammation-related cytokines including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b) and interleukin-6 (IL-6). The protein expression of TLR4 was positively correlated with the protein expression levels of MCP-1 (r ¼ 0.7863, p50.01) and TNF-a (r ¼ 0.7547, p50.01) in CKD rats. These findings indicated ozone therapy could attenuate tubulointerstitium inflammation injury in adenine-induced CKD rats and the mechanism might associate with the mediation of TLR4. ARTICLE HISTORY

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Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Cited by 43 publications

References 30 publications

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

Ozone therapy ameliorates tubulointerstitial inflammation by regulating TLR4 in adenine-induced CKD rats

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