Depletion of CD8+ T Cells Exacerbates CD4+ T Cell–Induced Monocyte-to-Fibroblast Transition in Renal Fibrosis

Dong, Yanjun; Yang, Min; Zhang, Jing; Peng, Xiaogang; Cheng, Jizhong; Cui, Taigeng; Du, Jie

doi:10.4049/jimmunol.1501232

Cited by 34 publications

(40 citation statements)

References 46 publications

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“…15,16 MMP9 activity was inhibited using MMP9 inhibitor or MMP9-neutralizing antibody, which was administered daily for four consecutive days from day 0 to 3 (for early stage of UUO), 6 to 9 (for mid stage) or 10 to 13 (for late stage). 1,10,[21][22][23][24] Therefore, we hypothesized that neutrophil infiltration enhances renal fibrosis by promoting the expansion of inflammation and macrophage accumulation in the obstructed kidney; moreover, neutrophil produces MMP9 in the kidney to promote macrophage infiltration. Many reports demonstrated that inflammatory cells, including neutrophils, produce MMP9 during tissue injury.…”

Section: Introductionmentioning

confidence: 99%

“…10,[17][18][19][20] Previous results by us and other researchers also demonstrated that the early stage of UUO is the progression of inflammatory cell infiltration, and a high peak occurred from days 3-7. 1,10,[21][22][23][24] Therefore, we hypothesized that neutrophil infiltration enhances renal fibrosis by promoting the expansion of inflammation and macrophage accumulation in the obstructed kidney; moreover, neutrophil produces MMP9 in the kidney to promote macrophage infiltration.…”

Section: Introductionmentioning

confidence: 99%

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MMP‐9‐positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice

Wang

Gao

et al. 2019

Acta Physiologica

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Aim: Matrix metalloproteinase-9 (MMP9) plays a profibrotic role in renal fibrosis. Neutrophils produce MMP9 in many pathologic models. However, the effect of neutrophil on the progression of renal fibrosis and the relationship of MMP9 to the infiltration of neutrophils into the kidney remain unknown. Methods: The surgery of unilateral ureter obstruction (UUO) was performed in male C57BL/6 mice. Kidneys were collected for analyses on days 0, 1, 3, 5 or 7 following surgery. The inflammatory cells were analysed by flow cytometry. The mRNA and protein levels of renal fibrosis factor and inflammatory factor were measured by qRT-PCR, immumofluorescence and western blot analysis. Results: In a mouse kidney model of UUO, neutrophil infiltration significantly increased and neutrophil accumulation reached the highest level at 5 days after the injury. In the obstructed kidney, depleting neutrophils decreased the expression of inflammatory factors, inhibited the accumulation of macrophages including type 2 macrophages and suppressed renal fibrosis. Almost all neutrophils produced MMP9 at the early stage of kidney obstruction. MMP9 attracted neutrophils and inflammatory cells because inhibiting MMP9 suppressed the infiltration of neutrophils and other inflammatory cells and reduced renal fibrosis, regardless of using MMP9 neutralizing antibody or MMP9 inhibitor or different intervening periods of days (0-6, 0-3 or 3-6 were applied after kidney obstruction). Conclusion: MMP9 promotes neutrophil infiltration by increasing the inflammatory level, macrophage accumulation and renal fibrosis in the obstructed kidney.Inhibiting MMP9 or depleting neutrophils in the early stage of acute kidney injury can relieve the progression of kidney fibrosis. K E Y W O R D Sfibrosis, inflammation, kidney, macrophage, neutrophil 2 of 13 | WANG et Al.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MMP‐9‐positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice

Wang

Gao

et al. 2019

Acta Physiologica

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“…In addition to the role of interstitial fibroblast proliferation, there were studies indicating that bone marrow-derived fibroblast precursors contributed significantly to the development of renal fibrosis [11, 12]. Previous research demonstrated that activation of proinflammatory cytokines contributed substantially to the development of renal interstitial fibrosis [13, 14]. Moreover, mounting evidence in vivo and in vitro has indicated that PTEN mediates multiple signal pathways involved in the pathophysiologic process of fibrosis in the kidney such as SMAD3, p53, and JNK[15, 16].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

Zhou

Zhong

Shi

et al. 2017

Cell Physiol Biochem

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Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

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“…To discover the reason why IRF‐1 can decrease Klotho transcription, we analyzed the sequence of putative promoter region of human Klotho gene. Bioinformatics analysis from all of the three databases (PROMO, Genecards and JASPAR) predicted 11 transcriptional factors that could bind to Klotho promoter region (the relative score is above 80 points) (Figure A).Nine transcriptional factors (C/EBP‐β, PPAR‐γ, p53, SP1, YY1, USF2, C/EBP‐α, GATA3, and ATF3) have been found to participate in renal fibrosis . Next, we detected which of the above transcription factors are regulated by IRF‐1 in tubular epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Nine transcriptional factors (C/EBP-β, PPAR-γ, p53, SP1, YY1, USF2, C/EBP-α, GATA3, and ATF3) have been found to participate in renal fibrosis. [30][31][32][33][34][35][36][37][38] Next, we detected which of the above transcription factors are regulated by IRF-1 in tubular epithelial cells. Our results show that mRNA level of four transcriptional factors (SP1, C/EBP-β, YY1, and C/EBP-α) were significantly changed after transfection with IRF-1 vector.…”

Section: Irf-1 Inhibits Klotho Expression Via Inactivation Of C/ebp-βmentioning

confidence: 99%

IRF‐1 promotes renal fibrosis by downregulation of Klotho

Liu

Huang

et al. 2020

FASEB j.

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Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF‐1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF‐1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF‐1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF‐1 repressed Klotho expression by downregulation of C/EBP‐β, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor‐alpha may be an important inducement for the increase of IRF‐1 in tubular epithelial cells after UUO and genetic deletion of IRF‐1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF‐1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF‐1 may be a potential therapeutic target for CKD.

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Depletion of CD8+ T Cells Exacerbates CD4+ T Cell–Induced Monocyte-to-Fibroblast Transition in Renal Fibrosis

Cited by 34 publications

References 46 publications

MMP‐9‐positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice

MMP‐9‐positive neutrophils are essential for establishing profibrotic microenvironment in the obstructed kidney of UUO mice

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

IRF‐1 promotes renal fibrosis by downregulation of Klotho

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