Involvement of YTHDF1 in renal fibrosis progression via up‐regulating YAP

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent different stages of renal failure; thus, CKD can be regarded as a result of AKI deterioration. Previous studies have demonstrated that immune cell infiltration, oxidative stress, and metabolic mentalism can support renal fibrosis progression in AKI cases. However, the most important triggers and cell types involved in this pathological progression remain unclear. This study was conducted to shed light into the underlying cellular and molecular features of renal fibrosis progression through the analysis of three mouse whole kidney and one human single-cell RNA-sequencing datasets publicly available. According to the different causes of AKI (ischemia reperfusion injury [IRI] or cisplatin), the mouse samples were divided into the CIU [control-IRI-unilateral ureteral obstruction (UUO)] and CCU (control-cisplatin-UUO) groups. Comparisons between groups revealed eight different modules of differentially expressed genes (DEGs). A total of 1,214 genes showed the same expression pattern in both CIU and CCU groups; however, 1,816 and 1,308 genes were expressed specifically in the CCU and CIU groups, respectively. Further assessment of the DEGs according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway and Gene Ontology (GO) showed that T-cell activation, fatty acid metabolic process, and arachidonic acid metabolism were involved in the fibrosis progression in CIU and CCU. Single-cell RNA-sequencing data along with the collected DEGs information also revealed that the T-cell activation mainly happened in immune cells, whereas the fatty acid metabolic process and arachidonic acid metabolism occurred in tubule cells. Taken together, these findings suggest that the fibrosis process differed between the CIU and CCU stages, in which immune and tubule cells have different functions. These identified cellular and molecular features of the different stages of fibrosis progression may pave the way for exploring novel potential therapeutic strategies in the clinic.

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SO041THE EFFECT AND MECAHNISM OF THE LOX IN AT1R/Β-ARRESTIN BIASED PATHWAY INDUCED RENAL INTERSTITIAL FIBROSIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa139.so041 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Xiaoqin Zhang ◽

Chen Yu

Keyword(s):

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Lysyl Oxidase ◽

Rat Kidney ◽

Ischemia Reperfusion ◽

Mek Inhibitor ◽

Collagen Crosslinking ◽

Fibrosis Progression

Abstract Background and Aims We studied the downstream and mechanism of β-arrestins signaling in renal fibrosis process and the role of lysyl oxidase (LOX) in the AT1R-β-arrestins pathway. Method The mechanism of β-arrestins signaling was studied in normal rat kidney tubule epithelial cells (NRK-52E) treated with SII in vitro. BAPN or placebo was administered during ischemia reperfusion (IR)-induced fibrosis progression. Collagen crosslinking and fibrosis progression were assessed histologically and biochemically. Results The mRNA and protein levels of β-arrestin-1 and β-arrestin-2 were significantly upregulated in renal fibrosis model both in vitro and in vivo. SII activated the ERK-STAT3 PY705 but not STAT3-Try727 in nucleus of NRK-52E cells, which effects were abolished when transfection of siRNA targeting β-arrestin-1 and β-arrestin-2 or pretreated with PD98059 (MEK inhibitor). LOX was strongly induced in fibrotic kidney and NRK-52E cells treated with SII. Active LOX significantly increased collagen crosslinking. In established IR-28d renal fibrosis, LOX inhibition promoted fibrosis reversal and with a 25% decrease insoluble collagen. Gene silencing of β-arrestin-1 + 2 or STAT3 apparently inhibited SII-induced LOX expression in vitro. Besides, chromatin immunoprecipitation (ChIP) assay clearly demonstrating the interaction between STAT3 and the LOX promoter, which indicated LOX is a direct target gene of SII-β-arrestins-STAT3 signaling. Conclusion The ERK/STAT3 was downstream of AT1R-β-arrestins, ERK entered the nucleus and activated STAT3-PY705. LOX mediates collagen crosslinking and fibrotic matrix stabilization during renal fibrosis via the AT1R-β-arrestins-ERK-STAT3-PY705 signaling. By blocking this profibrotic pathway, therapeutic LOX inhibition attenuates the fibrosis and suggesting target the LOX has significant potency for the treatment of patients with fibrotic kidney disorders.

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exploring mechanisms of renal fibrosis progression

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.93.0_2-s22-3 ◽

2020 ◽

Vol 93 (0) ◽

pp. 2-S22-3

Author(s):

Daisuke Nakano

Keyword(s):

Renal Fibrosis ◽

Fibrosis Progression

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Tacrolimus increases the expression level of the chemokine receptor CXCR2 to promote renal fibrosis progression

International Journal of Molecular Medicine ◽

10.3892/ijmm.2019.4368 ◽

2019 ◽

Author(s):

Dongdong Wang ◽

Xiao Chen ◽

Meng Fu ◽

Hong Xu ◽

Zhiping Li

Keyword(s):

Chemokine Receptor ◽

Renal Fibrosis ◽

Expression Level ◽

Fibrosis Progression ◽

Chemokine Receptor Cxcr2

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Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice

Biomedicines ◽

10.3390/biomedicines9070815 ◽

2021 ◽

Vol 9 (7) ◽

pp. 815

Author(s):

Beáta Róka ◽

Pál Tod ◽

Tamás Kaucsár ◽

Éva Nóra Bukosza ◽

Imre Vörös ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Target Prediction ◽

Time Points ◽

Fibrosis Progression ◽

Sham Surgery ◽

Injured Kidney

(1) Background: Ischemia reperfusion (IR) is the leading cause of acute kidney injury (AKI) and results in predisposition to chronic kidney disease. We demonstrated that delayed contralateral nephrectomy (Nx) greatly improved the function of the IR-injured kidney and decelerated fibrosis progression. Our aim was to identify microRNAs (miRNA/miR) involved in this process. (2) Methods: NMRI mice were subjected to 30 min of renal IR and one week later to Nx/sham surgery. The experiments were conducted for 7–28 days after IR. On day 8, multiplex renal miRNA profiling was performed. Expression of nine miRNAs was determined with qPCR at all time points. Based on the target prediction, plexin-A2 and Cd2AP were measured by Western blot. (3) Results: On day 8 after IR, the expression of 20/1195 miRNAs doubled, and 9/13 selected miRNAs were upregulated at all time points. Nx reduced the expression of several ischemia-induced pro-fibrotic miRNAs (fibromirs), such as miR-142a-duplex, miR-146a-5p, miR-199a-duplex, miR-214-3p and miR-223-3p, in the injured kidneys at various time points. Plexin-A2 was upregulated by IR on day 10, while Cd2AP was unchanged. (4) Conclusion: Nx delayed fibrosis progression and decreased the expression of ischemia-induced fibromirs. The protein expression of plexin-A2 and Cd2AP is mainly regulated by factors other than miRNAs.

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The Role of Renal Macrophage, AIM, and TGF-β1 Expression in Renal Fibrosis Progression in IgAN Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.646650 ◽

2021 ◽

Vol 12 ◽

Author(s):

Min Yang ◽

Jia Wei Liu ◽

Yu Ting Zhang ◽

Gang Wu

Keyword(s):

Renal Fibrosis ◽

Renal Tissue ◽

Normal Control Group ◽

Control Group ◽

M2 Macrophage ◽

M2 Macrophages ◽

Normal Renal Tissue ◽

Fibrosis Progression ◽

Tgf Β1

ObjectiveTo analyze the expression of macrophages, AIM, TGF-β1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-β1 in the progression of renal fibrosis in IgAN patients.MethodsThe paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-β1 by immunohistochemical staining and/or immunofluorescence.ResultThe number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-β1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-β1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-β1 were positively correlated with fibrotic area.ConclusionM2 macrophages, AIM and TGF-β1 play important roles in the process of IgAN fibrosis, and the three influence each other.

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