scholarly journals Depletion of Fractalkine ameliorates renal injury and Treg cell apoptosis via the p38MAPK pathway in lupus-prone mice

2021 ◽  
pp. 112704
Author(s):  
Jingxue Ma ◽  
Qiming Gong ◽  
Xiuhong Pan ◽  
Pengwei Guo ◽  
Linlin He ◽  
...  
Keyword(s):  
Treg Cell ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
P38mapk Pathway

scholarly journals Depletion of Fractalkine Ameliorates Renal Injury and Treg Cell Apoptosis Via the p38MAPK Pathway in Lupus-prone Mice

2020 ◽  
Author(s):  
Jingxue Ma ◽  
Qiming Gong ◽  
Pengwei Guo ◽  
Xiuhong Pan ◽  
Linlin He ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Treg Cell ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Opposite Effect ◽  
Treg Cells ◽  
Signalling Pathway ◽  
Cyt C ◽  
P38mapk Pathway ◽  
Protein Serum

Abstract Background: Fractalkine is a chemokine with several roles, including chemotaxis, adhesion, and immune damage. It participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. On the other hand, Treg cells are involved in autoimmune diseases. This study aimed to explore the regulatory mechanism of Fractalkine in renal injury and Treg apoptosis via the p38MAPK signalling pathway in lupus-prone mice. Methods: Lupus was induced in BALB/c female mice by injection of pristane. Then, CD4+ CD5+ Treg cells were isolated from the spleen of lupus mice. To deplete Fractalkine, first, mice received an injection of anti-Fractalkine antibody. Later, the transfection of Treg cells with Fractalkine siRNA was conducted. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and/or activator U-46619, respectively. The levels of urine protein, serum urea nitrogen, creatinine, and autoantibodies were measured from mouse samples, and renal histopathological features were analysed. The expression of Fractalkine, p-p38, Foxp3, IL-6, and IL-17 in the mouse kidney and Treg cells was detected. The levels of apoptosis and key apoptotic factors: Bax, Bcl-2, and Cyt-c in Treg cells were analysed. Results: The expression of Fractalkine, p-p38, IL-6, and IL-17 increased; meanwhile, that of Foxp3 decreased in the kidneys of mice with lupus. The depletion of Fractalkine and p38MAPK levels ameliorated proteinuria and renal functions and significantly reduced serum autoantibodies, renal Fractalkine, p-p38, IL-6, and IL-17 levels, while increasing renal Foxp3 concentration in lupus mice. The effects of Fractalkine knockdown (KD) and p38MAPK inhibitor on Treg cells, derived from lupus mice, were consistent with those observed in the kidneys. In addition, Fractalkine KD reduced cell apoptosis and suppressed the activation of p38MAPK signalling in Treg cells, derived from lupus mice. Meanwhile, the p38MAPK activator U-46619 had the opposite effect. Conclusion: Together, our data indicated that Fractalkine promoted the nephritis progression in lupus mice, most likely through the regulation of Treg cell apoptosis and activation of the p38MAPK signalling pathway. It suggested that targeting Fractalkine is a potential therapeutic strategy for treating LN.

scholarly journals Depletion of Fractalkine Ameliorates Renal Injury and Treg Cell Apoptosis via the p38MAPK Pathway in Lupus-Prone Mice

2020 ◽  
Author(s):  
Jingxue Ma ◽  
Qiming Gong ◽  
Pengwei Guo ◽  
Xiuhong Pan ◽  
Linlin He ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Treg Cell ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Opposite Effect ◽  
Treg Cells ◽  
Signalling Pathway ◽  
Cyt C ◽  
P38mapk Pathway ◽  
Protein Serum

Abstract Background Fractalkine is a chemokine with several roles, including chemotaxis, adhesion, and immune damage. It participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. On the other hand, Treg cells are involved in autoimmune diseases. This study aimed to explore the regulatory mechanism of Fractalkine in renal injury and Treg apoptosis via the p38MAPK signalling pathway in lupus-prone mice. Methods Lupus was induced in BALB/c female mice by injection of pristane. Then, CD4+ CD5+ Treg cells were isolated from the spleen of lupus mice. To deplete Fractalkine, first, mice received an injection of anti-Fractalkine antibody. Later, the transfection of Treg cells with Fractalkine siRNA was conducted. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and/or activator U-46619, respectively. The levels of urine protein, serum urea nitrogen, creatinine, and autoantibodies were measured from mouse samples, and renal histopathological features were analysed. The expression of Fractalkine, p-p38, Foxp3, IL-6, and IL-17 in the mouse kidney and Treg cells was detected. The levels of apoptosis and key apoptotic factors: Bax, Bcl-2, and Cyt-c in Treg cells were analysed. Results The expression of Fractalkine, p-p38, IL-6, and IL-17 increased; meanwhile, that of Foxp3 decreased in the kidneys of mice with lupus. The depletion of Fractalkine and p38MAPK levels ameliorated proteinuria and renal functions and significantly reduced serum autoantibodies, renal Fractalkine, p-p38, IL-6, and IL-17 levels, while increasing renal Foxp3 concentration in lupus mice. The effects of Fractalkine knockdown (KD) and p38MAPK inhibitor on Treg cells, derived from lupus mice, were consistent with those observed in the kidneys. In addition, Fractalkine KD reduced cell apoptosis and suppressed the activation of p38MAPK signalling in Treg cells, derived from lupus mice. Meanwhile, the p38MAPK activator U-46619 had the opposite effect. Conclusion Together, our data indicated that Fractalkine promoted the nephritis progression in lupus mice, most likely through the regulation of Treg cell apoptosis and activation of the p38MAPK signalling pathway. It suggested that targeting Fractalkine is a potential therapeutic strategy for treating LN.

MDM2 inhibition improves cisplatin-induced renal injury in mice via inactivation of Notch/hes1 signaling pathway

2020 ◽  
pp. 096032712095215
Author(s):  
X Luo ◽  
L Zhang ◽  
G-D Han ◽  
P Lu ◽  
Y Zhang
Keyword(s):  
Signaling Pathway ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Renal Tissue ◽  
Tunel Staining ◽  
Acute Renal Injury ◽  
Renal Tubular ◽  
Injury Models

Objective: To explore the potential function of MDM2-mediated Notch/hes1 signaling pathway in cisplatin-induced renal injury. Methods: The acute renal injury models of mice after intraperitoneal injection of cisplatin in vivo, and the apoptotic models of human renal tubular epithelial (HK-2) cells induced by cisplatin in vitro, were conducted respectively. The renal function-related parameters were measured. The renal tissue pathological changes and apoptosis were observed by PAS staining and TUNEL staining, respectively. Cell viability and apoptosis were detected by MTT and flow cytometry. Notch/hes1 pathway-related proteins were tested by Western blotting. Results: After mice injected by cisplatin, the levels of Cr, BUN, urine cystatin C, urine NGAL and urine ACR were increased and GFR was decreased with the elevation of renal tubular injury scores, the upregulation of the expressions of MDM2, N1ICD, Hes1 and Cleaved caspase-3, as well as the enhancement of cell apoptosis accompanying decreased ratio of Bcl-2/Bax. However, these cisplatin-induced renal injuries of mice have been improved by MDM2 inhibition. Besides, the declined viability, increased cytotoxicity, and enhanced apoptosis were observed in cisplatin-induced HK-2 cells, with the activated Notch/hes1 pathway. Notably, the phenomenon was alleviated in cisplatin-induced HK-2 cells transfected with MDM2 shRNA, but was severer in those co-treated with AdMDM2. Moreover, Notch1 siRNA can reverse the injury of AdMDM2 on HK-2 cells. Conclusion: Inhibiting MDM2 could reduce cell apoptosis through blocking Notch/hes1 signaling pathway, thus alleviating the acute renal injury caused by cisplatin.

scholarly journals LncRNA-ATB Participates in the Regulation of Calcium Oxalate Crystal-induced Renal Injury by Sponging the miR-200 Family

2021 ◽  
Author(s):  
Yinhui Li ◽  
Tao Ding ◽  
Haiyan Hu ◽  
Tingting Zhao ◽  
Chao Zhu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Calcium Oxalate ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Proliferation Inhibition ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Caox Crystal ◽  
Tgf Β1

Abstract Background: LncRNA-ATB is a long noncoding RNAs (lncRNA) activated by transforming growth factor β (TGF-β) and it has important biological functions in tumours and nontumor diseases. Meanwhile, TGF-β is the most critical regulatory factor in the process of nephrotic fibrosis and calcium oxalate (CaOx) crystal-induced renal injury. The present study aimed to investigate the biological function and mechanism of lncRNA-ATB in CaOx crystal-induced renal injury. Methods: The expression level of lncRNA-ATB was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), the expression levels of epithelial-mesenchymal transition (EMT) markers and TGF-β1 were detected by qRT-PCR and western bloting, cell proliferation was measured with the CCK-8 kit, cell apoptosis was measured by flow cytometry, and cell injury was detected with the Cytotoxicity lactate dehydrogenase (LDH) Assay kit.Results: The expression levels of lncRNA-ATB and TGF-β1 significantly increased in HK-2 cells after coincubation with calcium oxalate monohydrate (COM). COM stimulation caused significant injury in HK-2 cells, induced cell apoptosis, inhibited cell proliferation, and induced EMT changes . After COM stimulation, the expression levels of epithelial cell markers E-cadherin and zonula occludens (ZO)-1 in HK-2 cells significantly decreased, whereas the levels of mesenchymal cell markers N-cadherin and vimentin significantly increased. Interference with lncRNA-ATB expression significantly relieved COM-induced cell injury, cell apoptosis, proliferation inhibition, and EMT changes. The expression levels of the microRNA-200 (miR-200) family in HK-2 cells after coincubation with COM significantly decreased. MiR-200a mimics relieved the COM-induced cell injury, apoptosis, proliferation inhibition, and EMT changes, whereas miR-200a inhibitors abolished the lncRNA-ATB interference-induced relief of COM-induced cell injury, apoptosis, proliferation inhibition, and EMT. Conclusion: lncRNA-ATB promote d COM-induced cell injury, cell apoptosis, proliferation inhibition, and EMT to participate in the process of CaOx crystal-induced renal injury by sponging miR-200s.

MicroRNA-10a-3p mediates Th17/Treg cell balance and improves renal injury by inhibiting REG3A in lupus nephritis

2020 ◽  
Vol 88 ◽  
pp. 106891
Author(s):  
Guanqiao You ◽  
Huixia Cao ◽  
Lei Yan ◽  
Pan He ◽  
Yanliang Wang ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Treg Cell ◽  
Renal Injury ◽  
Cell Balance

The protective role of telmisartan against nephrotoxicity induced by X-ray contrast media in rat model

2009 ◽  
Vol 50 (7) ◽  
pp. 754-759 ◽  
Author(s):  
Shao Bin Duan ◽  
Yu Hui Wang ◽  
Fu You Liu ◽  
Xiang Qing Xu ◽  
Pian Wang ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Contrast Media ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Renal Tissue ◽  
Protective Role ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

Background: Contrast-induced nephropathy is a serious complication of diagnostic and interventional procedures. Purpose: To evaluate the nephrotoxicity of high- and low-osmolar contrast media (HOCM, LOCM) on kidneys in Sprague-Dawley rats. Telmisartan was administered to confirm its protective role against nephrotoxicity induced by contrast media. Material and Methods: Sixty male rats were randomly divided into six groups ( n=10/group). Glycerin was given to all rats except controls to induce renal injury. HOCM (diatrizoate) or LOCM (iohexol) (10 ml/kg b.w., 300 mg I/ml) was given through a caudal vein. Serum creatinine level was measured by an automatical biochemical analyzer. Caspase-3 activity and Angiotensin II (Ang II) level of renal tissue were detected by fluorometric method and radioimmunoassay, respectively. The renal injury was also assessed by hematoxylin and eosin and TdT-mediated deoxyuridine nick end-labeling staining. Results: In diatrizoate-injected rats, serum creatinine level was increased ( P<0.001). There was no significant difference between iohexol animals and glycerol controls in the level of serum creatinine. The renal caspase-3 activity and Ang II levels in HOCM and LOCM groups were higher than those in glycerol control group ( P<0.001). The percentage of apoptotic tubular cells and pathological scores were lower in the iohexol animals than that in the diatrizoate animals ( P<0.001). In the groups pretreated with telmisartan, no increase in the levels of serum creatinine, renal Ang II, and caspase-3 activity was observed ( P>0.05). The renal injuries induced by contrast media were alleviated. Conclusion: Both HOCM (diatrizoate) and LOCM (iohexol) could cause renal tubular cell apoptosis in the kidneys damaged by glycerin. LOCM was less toxic to rat kidneys than HOCM. Caspase-3 and Ang II might play a role in renal tubular cell apoptosis induced by contrast media. Telmisartan protected the renal tissue from nephrotoxicity induced by contrast media.

scholarly journals NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury

2019 ◽  
Vol 316 (2) ◽  
pp. F382-F395 ◽  
Author(s):  
Dan Xu ◽  
Panpan Chen ◽  
Bao Wang ◽  
Yanzhe Wang ◽  
Naijun Miao ◽  
...  
Keyword(s):  
Renal Injury ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Common Symptom ◽  
Renal Tubules ◽  
Renal Tubular

Proteinuria, the most common symptom of renal injury, is an independent factor for renal tubular injury. However, the underlying mechanism remains to be fully elucidated. Mitochondrion is an important target for proteinuria-induced renal tubular cell injury. Insufficient mitophagy exacerbates cell injury by initiating mitochondrial dysfunction-related cell apoptosis. In the experiment, the role of NIP3-like protein X (NIX)-mediated mitophagy was investigated in proteinuria-induced renal injury. In this study, we demonstrated that NIX expression was reduced in renal tubules and correlated with the decline of estimated glomerular filtration rate and increase of the proteinuria in patients. In proteinuric mice, NIX-mediated mitophagy was significantly suppressed. Meanwhile, the proteinuric mice exhibited renal dysfunction, increased mitochondrial fragmentation, and tubular cell apoptosis. Overexpression of NIX attenuated those disruptions in proteinuric mice. In cultured renal tubular epithelial cells, albumin induced a decrease in NIX-mediated mitophagy and an increase in cell apoptosis. Overexpression of NIX attenuated albumin-induced cell apoptosis, whereas NIX siRNA aggravated these perturbations. These results indicate that proteinuria suppresses NIX-mediated mitophagy in the renal tubular epithelial cell, which triggers the cell undergoing mitochondria-dependent cell apoptosis. Collectively, our finding suggests that restoration of NIX-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury.

scholarly journals Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110126
Author(s):  
Deyuan Zhi ◽  
Meng Zhang ◽  
Jin Lin ◽  
Pei Liu ◽  
Yajun Wang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Inflammatory Cytokines ◽  
Protein Tyrosine Phosphatase ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Tyrosine Phosphatase ◽  
Receptor Type ◽  
Dependent Manner ◽  
Protein Tyrosine

Objective To explore the effects of wedelolactone (WEL) on sepsis-induced renal injury in the human renal proximal tubular epithelial cell line HK-2. Methods HK-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) to trigger renal injury in vitro. HK-2 cells were pretreated with or without WEL (0.1, 1 and 10 µM) before LPS stimulation. Protein and mRNA analyses were performed using enzyme-linked immunosorbent assays, Western blot analysis and quantitative reverse transcription–polymerase chain reaction. The MTT assay and flow cytometry were used to measure cell viability and the rate of cell apoptosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) knockdown was induced by the transection of HK-2 cells with short hairpin RNA. Results Cell viability was significantly increased in a dose-dependent manner by WEL in LPS-induced HK-2 cells. WEL also decreased the levels of four inflammatory cytokines and cell apoptosis in LPS-induced HK-2 cells. The level of PTPN2 was increased after WEL treatment. PTPN2 knockdown partly abolished the inhibitory effects of WEL on cell apoptosis, the levels of inflammatory cytokines and on p38 mitogen-activated protein kinase/nuclear factor-kappaB signalling in LPS-induced HK-2 cells. Conclusion WEL improved renal injury by suppressing inflammation and cell apoptosis through upregulating PTPN2 in HK-2 cells. PTPN2 might be used as a potential therapeutic target for LPS-induced sepsis.

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