FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Tian, Tongguan; Zhang, Jun; Zhu, Xingxing; Wen, Shuang; Shi, Dongyan; Zhou, Hong

doi:10.1111/cei.13003

Cited by 27 publications

(15 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to previous studies and our CCK-8 results, 10 ng/mL TGF-β1 was used to activate fibroblasts; 1, 2, and 4 mg/mL were selected as the low-, moderate- and high-doses of SK; and 48 h was selected as the intervention time in the present study. Upregulation of α-SMA and morphological changes accompanied by cell proliferation and activation, which manifested as increases in cell viability and ECM production, occurred in NRK-49F cells after TGF-β1 stimulation [ 26 , 27 ]. In this study, it was confirmed that TGF-β1 regulated the gene expression of α-SMA and ECM by activating the upstream JAK2/STAT3 pathway.…”

Section: Discussionmentioning

confidence: 99%

Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway

Qin

Liu

et al. 2021

BMC Complement Med Ther

View full text Add to dashboard Cite

Background Activation of renal fibroblasts is a critical mechanism in the process of renal fibrosis. As a commonly used herbal formula, Shenkang (SK) has been found to attenuate renal fibrosis and renal parenchyma destruction. However, the effect of SK on renal fibroblast activation in unilateral ureteral obstruction (UUO) mice and its molecular mechanism remain undetermined. The present study was performed to elucidate the effect of SK on renal fibroblast activation and renal fibrosis, as well as the potential underlying mechanism, in both NRK-49F cells and UUO mice. Methods NRK-49F cells were stimulated with 10 ng/ml TGF-β1 for 48 h. After SK treatment, the CCK-8 method was used to evaluate cell viability. Thirty-six C57BL/6 mice were randomly divided into the sham group, UUO group, angiotensin receptor blocker (ARB) group, and SK high-, moderate- and low-dose groups. UUO was induced in mice except those in the sham group. Drugs were administered 1 day later. On the 13th day, the fractional anisotropy (FA) value was determined by MRI to evaluate the degree of renal fibrosis. After 14 days, serum indexes were assessed. Hematoxylin and eosin (HE) and Sirius red staining were used to observe pathological morphology and the degree of fibrosis of the affected kidney. Western blotting and PCR were used to assess the expression of related molecules in both cells and animals at the protein and gene levels. Results Our results showed that SK reduced extracellular matrix (ECM) and α-smooth muscle actin (α-SMA) expression both in vitro and in vivo and attenuated renal fibrosis and the pathological lesion degree after UUO, suppressing JAK2/STAT3 activation. Furthermore, we found that SK regulated the JAK2/STAT3 pathway regulators peroxiredoxin 5 (Prdx5) in vitro and suppressor of cytokine signaling protein 1 (SOCS1) and SOCS3 in vivo. Conclusions These results indicated that SK inhibited fibroblast activation by regulating the JAK2/STAT3 pathway, which may be a mechanism underlying its protective action in renal fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway

Qin

Liu

et al. 2021

BMC Complement Med Ther

View full text Add to dashboard Cite

show abstract

“…In addition, we recently demonstrated that ApoM/S1P possesses protective properties against LPS‐induced renal injuries through their antiapoptotic properties (44). Regarding models of chronic kidney diseases, however, the roles of S1P have yet to be established, and the involvement of ApoM has not been studied, although S1P has been demonstrated to possess profibrotic properties (45–47). Therefore, investigation of the roles of S1P in chronic kidney diseases, especially using in vivo experiments, is needed.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

et al. 2019

View full text Add to dashboard Cite

Because the association between sphingosine 1‐phosphate (S1P)/apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involvement of S1P/ApoM in the phenotypes of IgA nephropathy in hyper‐IgA (HIGA) mice. The overexpression of ApoM in adenoviral gene transfer ameliorated the phenotypes of IgA nephropathy in HIGA mice, whereas the knockdown of ApoM with siRNA caused deterioration. When ApoM‐overexpressing HIGA mice were treated with VPC23019, an antagonist against S1P receptor 1 (S1P1) and 3 (S1P3), we observed that the protective effects of ApoM were reversed, whereas JTE013, an antagonist against S1P2, did not inhibit the effects. We also found that S1P bound to albumin accelerated the proliferation of MES13 cells and the fibrotic changes of HK2 cells, which were inhibited by JTE013, whereas S1P bound to ApoM suppressed these changes, which were inhibited by VPC23019. These results suggest that S1P bound to ApoM possesses properties protective against the phenotypes of IgA nephropathy through S1P1 and S1P3, whereas S1P bound to albumin exerts deteriorating effects through S1P2. ApoM may be useful as a therapeutic target to treat or retard the progression of IgA nephropathy.—Kurano, M., Tsuneyama, K., Morimoto, Y., Nishikawa, M., Yatomi, Y. Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice. FASEB J. 33, 5181–5195 (2019). http://www.fasebj.org

show abstract

“…Additionally, by attenuating expression of intrarenal angiotensin II and AT1R, a combination of telmisartan and pitavastatin could inhibit renal fibrosis and inflammation by suppressing activations of TGF-β1-Smad and NF-κB [110]. Fingolimod (FTY720), an analogue of sphingosine 1-phosphate, has been shown to attenuate collagen deposition, inflammation and tubulo-interstitial fibrosis in UUO mice [175]. Furthermore, FTY720 mitigated TGF-βmediated α-SMA expression and collagen synthesis by inhibiting both Smad2/3 and PI3K/AKT/glycogen synthase kinase 3 beta pathways in NRK-49F cells [175].…”

Section: Selective Inhibition Of Smads Signalingmentioning

confidence: 99%

“…Fingolimod (FTY720), an analogue of sphingosine 1-phosphate, has been shown to attenuate collagen deposition, inflammation and tubulo-interstitial fibrosis in UUO mice [175]. Furthermore, FTY720 mitigated TGF-βmediated α-SMA expression and collagen synthesis by inhibiting both Smad2/3 and PI3K/AKT/glycogen synthase kinase 3 beta pathways in NRK-49F cells [175]. Ki16425, a LPA receptor 1/3 antagonist, has been shown to block upregulation of TGF-β1 expression and Smad2/3 phosphorylation in SV40 MES13 cells by lysophosphatidic acid stimulation and in db/db mice [176].…”

Section: Selective Inhibition Of Smads Signalingmentioning

confidence: 99%

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

277

200

View full text Add to dashboard Cite

Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

show abstract

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Cited by 27 publications

References 36 publications

Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway

Effect of Shenkang on renal fibrosis and activation of renal interstitial fibroblasts through the JAK2/STAT3 pathway

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Contact Info

Product

Resources

About