scholarly journals Transforming growth factor-β1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction

2000 ◽  
Vol 58 (5) ◽  
pp. 1885-1892 ◽  
Author(s):  
Yoshitaka Isaka ◽  
Michiko Tsujie ◽  
Yutaka Ando ◽  
Hiroyuki Nakamura ◽  
Yasufumi Kaneda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ureteral Obstruction ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β1 ◽  
Unilateral Ureteral Obstruction ◽  
Antisense Oligodeoxynucleotides

scholarly journals Renoprotective Effects of Maslinic Acid on Experimental Renal Fibrosis in Unilateral Ureteral Obstruction Model via Targeting MyD88

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjuan Sun ◽  
Chang Hyun Byon ◽  
Dong Hyun Kim ◽  
Hoon In Choi ◽  
Jung Sun Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Adaptor Protein ◽  
Tissue Growth ◽  
Unilateral Ureteral Obstruction ◽  
Maslinic Acid

Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-β in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-β treated NRK49F cells (p < 0.05, respectively). Notably, MA specifically interferes with MyD88, an adaptor protein, thereby mitigating Smad4 nuclear expression (p < 0.01 compared to TGF-β treated group) and ameliorating renal fibrotic changes (p < 0.01 for each fibrotic markers compared to TGF-β induced cells). In addition, in the UUO model and lipopolysaccharide-induced NRK49F cells, MA treatment decreased the expression of IL-1β, TGF-α and MCP-1, ICAM-1, associated with the suppression of NF-κB signaling. These findings suggest that MA is a potential agent that can reduce renal interstitial fibrosis, to some extent, via targeting TGF-β/Smad and MyD88 signaling.

scholarly journals Bone Morphogenetic Protein-2 Antagonizes Renal Interstitial Fibrosis by Promoting Catabolism of Type I Transforming Growth Factor-β Receptors

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 727-740 ◽  
Author(s):  
Yu-Lin Yang ◽  
Yi-Shiuan Liu ◽  
Lea-Yea Chuang ◽  
Jinn-Yuh Guh ◽  
Tao-Chen Lee ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ureteral Obstruction ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Morphogenetic Protein ◽  
Tgf Β1

TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-β1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-β1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-β receptors (TGF-β RI). Moreover, BMP-2 significantly shortened the half-life of TGF-β RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-β RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-β RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-β. We demonstrated that BMP-2 significantly reversed the TGF-β1-induced increase in pSmad2/3 and reversed the TGF-β1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-β RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson’s trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-β RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-β RI and Smads. Bone morphogenetic protein-2 can antagonize TGF-β-inducing cellular fibrosis by intervening post-receptors signaling, thus disclosing an application of therapeutical potential against fibrosis disorders.

scholarly journals Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction

2019 ◽  
Vol 34 (12) ◽  
pp. 2042-2050 ◽  
Author(s):  
Lan Yao ◽  
M Frances Wright ◽  
Brandon C Farmer ◽  
Laura S Peterson ◽  
Amir M Khan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Plasminogen Activator ◽  
Ureteral Obstruction ◽  
Interstitial Fibrosis ◽  
Plasminogen Activator Inhibitor ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Epithelium ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Background Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1). Methods Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later. Results GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice. Conclusion These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.

scholarly journals SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction

2016 ◽  
Vol 311 (3) ◽  
pp. F614-F625 ◽  
Author(s):  
Maria Mustafa ◽  
Tony N. Wang ◽  
Xing Chen ◽  
Bo Gao ◽  
Joan C. Krepinsky
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ureteral Obstruction ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Fibrotic Process ◽  
Atubular Glomeruli ◽  
Tgf Β1

Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.

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