TGF-β1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways

Ahmad, Saeed Nazari Soltan; Kalantary‐Charvadeh, Ashkan; Hamzavi, Masoud; Ezzatifar, Fatemeh; Beilankouhi, Elmira Aboutalebi Vand; Toofani-Milani, Attabak; Geravand, Faezeh; Golshadi, Zakieh; Mesgari‐Abbasi, Mehran

doi:10.1007/s10735-022-10078-6

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…Consistent with an increased the abundance of myofibroblasts, UUO is known to markedly increases abundance of the key matrix proteins tissue fibronectin, collagen 1 and collagen 3 (Ahmad et al., 2022). We confirmed that fibronectin, which is a prerequisite for the fibrotic process, was still increased in the tissue 7 days after UUO (Figure 4) and this increase was observed in both males and females.…”

Section: Resultsmentioning

confidence: 97%

P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

Therkildsen,

Tingskov,

Jensen

et al. 2023

Physiological Reports

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Renal fibrosis is tightly associated with chronic kidney disease, irrespective of the underlying pathogenesis. We previously demonstrated mild antifibrotic effects of targeting the P2X7 receptor in a pyelonephritis model. Reduced P2X7R‐activation elevated the neutrophil‐to‐macrophage ratio, resulting in less matrix accumulation without affecting the initial tissue healing. Here, we test if this P2X7R‐dependent modification of matrix accumulation also applies to a noninfectious fibrosis model of unilateral ureteral obstruction (7dUUO) and whether the response is gender‐dependent. We found that P2X7−/− mice show reduced fibrosis compared to wild type after 7dUUO: the effect was most pronounced in females, with a 55% decrease in collagen deposition after 7dUUO (p < 0.0068). P2X7R deficiency did not affect early fibrosis markers (TGF‐β, α‐SMA) or the renal infiltration of neutrophils. However, a UUO‐induced increase in macrophages was observed in wildtypes only (p < 0.001), leaving the P2X7−/− mice with ≈50% fewer CD68+ cells in the renal cortex (p = 0.018). In males, 7dUUO triggered an increase in diffusely interstitial scattering of the profibrotic, macrophage‐attracting metalloproteinase MMP8 and showed significantly lower MMP8 tissue expression in both male and female P2X7−/− mice (p < 0.0008). Thus, the P2X7R is advocated as a late‐stage fibrosis moderator by reducing neutrophil‐dependent interstitial MMP8 release, resulting in less macrophage infiltration and reduced matrix accumulation.

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Section: Resultsmentioning

confidence: 97%

P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

Therkildsen,

Tingskov,

Jensen

et al. 2023

Physiological Reports

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“…The results showed that there were interactions between these genes(see image below). TGF-β1 receptor blockade can prevent UUO-induced renal fibrosis by indirectly regulating the Smad and MAPK signaling pathways [ 56 ]. Overexpression of miR-499a leads to the inhibition of glioma cell proliferation and inhibition of the MAPK signaling pathway by reducing NOTCH1 to promote cell apoptosis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of key biomarkers of the glomerulus in focal segmental glomerulosclerosis and their relationship with immune cell infiltration based on WGCNA and the LASSO algorithm

Zhang

Bai

et al. 2023

Renal Failure

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Objective The aim of our study was to identify key biomarkers of glomeruli in focal glomerulosclerosis (FSGS) and analyze their relationship with the infiltration of immune cells. Methods The expression profiles (GSE108109 and GSE200828) were obtained from the GEO database. The differentially expressed genes (DEGs) were filtered and analyzed by gene set enrichment analysis (GSEA). MCODE module was constructed. Weighted gene coexpression network analysis (WGCNA) was performed to obtain the core gene modules. Least absolute shrinkage and selection operator (LASSO) regression was applied to identify key genes. ROC curves were employed to explore their diagnostic accuracy. Transcription factor prediction of the key biomarkers was performed using the Cytoscape plugin IRegulon. The analysis of the infiltration of 28 immune cells and their correlation with the key biomarkers were performed. Results A total of 1474 DEGs were identified. Their functions were mostly related to immune-related diseases and signaling pathways. MCODE identified five modules. The turquoise module of WGCNA had significant relevance to the glomerulus in FSGS. TGFB1 and NOTCH1 were identified as potential key glomerular biomarkers in FSGS. Eighteen transcription factors were obtained from the two hub genes. Immune infiltration showed significant correlations with T cells. The results of immune cell infiltration and their relationship with key biomarkers implied that NOTCH1 and TGFB1 were enhanced in immune-related pathways. Conclusion TGFB1 and NOTCH1 may be strongly correlated with the pathogenesis of the glomerulus in FSGS and are new candidate key biomarkers. T-cell infiltration plays an essential role in the FSGS lesion process.

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“…9) Several studies confirmed that the mitogen-activated protein kinase (MAPK) signaling pathways are directly activated by TGF-β1. 10) Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK) and P38 has been shown to directly phosphorylate the linker region of Smad2/3 and increase their duration of transcriptional activity. 11,12) Furthermore, activated ERK has been demonstrated to increase the level of Snail, thereby reducing the expression of E-cadherin and stimulating the incidence of EMT.…”

Section: Introductionmentioning

confidence: 99%

Linagliptin Mitigates TGF-β1 Mediated Epithelial–Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis <i>via</i> Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways

Nady,

Abd El-Raouf,

El-Sayed

2024

Biological & Pharmaceutical Bulletin

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The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin's (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows:The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial-mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor β1 (TGF-β1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-β1 mediated EMT via Smad-dependent and independent signaling pathways.

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TGF-β1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways

Cited by 8 publications

References 26 publications

P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

Identification of key biomarkers of the glomerulus in focal segmental glomerulosclerosis and their relationship with immune cell infiltration based on WGCNA and the LASSO algorithm

Linagliptin Mitigates TGF-β1 Mediated Epithelial–Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis <i>via</i> Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways

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TGF-β1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways

Cited by 8 publications

References 26 publications

P2X7 accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

P2X7 accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

Identification of key biomarkers of the glomerulus in focal segmental glomerulosclerosis and their relationship with immune cell infiltration based on WGCNA and the LASSO algorithm

Linagliptin Mitigates TGF-β1 Mediated Epithelial–Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis <i>via</i> Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways

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P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction

P2X₇ accelerate tissue fibrosis via metalloproteinase 8‐dependent macrophage infiltration in a murine model of unilateral ureteral obstruction