scholarly journals Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling

2013 ◽  
Vol 304 (8) ◽  
pp. F1054-F1065 ◽  
Author(s):  
Punithavathi Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Transgenic Animals ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

scholarly journals MO339KIDNEY DERIVED APOM AND ITS ROLE IN ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Line Stattau Bisgaard ◽  
Pernille M Christensen ◽  
Ernst-Martin Füchtbauer ◽  
Lars Bo Nielsen ◽  
Christina Christoffersen
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Abstract Background and Aims Acute kidney injury is a severe disease with detrimental outcomes. The underlying ethiology is still elusive and besides dialysis, treatment options are poor. Apolipoprotein M (apoM) is mainly expressed in liver and in proximal tubular epithelial cells in the kidney. In plasma, apoM associates with HDL particles via a retained signal peptide. ApoM is a carrier of sphingosine-1-phosphate (S1P), a small bioactive lipid involved in e.g. angiogenesis, lymphocyte trafficking, and vascular barrier function. Recently, it was shown that apoM/S1P protects against development of liver and lung fibrosis. In urine, apoM is normally undetectable in both wild type mice and healthy humans. However, lack of megalin receptors in proximal tubuli induces loss of apoM into the urine. The biological function of kidney-derived apoM is unknown, but it has been hypothesized that apoM might be secreted to the pre-urine to sequester molecules, such as S1P, from secretion. The aim of this study was to unravel the role of apoM in kidney biology and in acute kidney injury. Method A novel kidney specific human apoM transgenic mouse (RPTEC-hapoMTG), was generated by expressing human apoM under the control of the proximal tubular epithelial cell specific Sglt2 promoter. The effect of kidney specific apoM overexpression on acute kidney injury was accessed by inducing either cisplatin or ischemia/reperfusion injury. Further, a stable cell line of HK-2 cells overexpressing hapoM (HK-2hapoM-TG) was generated and the cells were cultured on transwells to assess the secretion of apoM to respectively the apical and basolateral site. Results hapoM was present in plasma from RPTEC-hapoMTG mice (mean 0.18 μM), indicating that kidney-derived apoM can be secreted to plasma. When assessing the secretion of hapoM from proximal tubular epithelial cells in vitro, studies support that apoM can be secreted to both the apical (urine) and basolateral (blood) compartment. No differences in kidney injury markers (plasma urea and creatinine) between RPTEC-hapoMTG and wild type (WT) mice subjected to cisplatin injections, or in kidney injury score determined by histological evaluation was found. Similar, we could not detect any histological difference between RPTEC-hapoMTG and WT mice after ischemia/reperfusion injury, and overexpression of hapoM did not affect kidney gene expression of inflammatory markers (i.e. IL6, MCP-1) compared to WT mice. Conclusion Our study suggests that apoM can be secreted to both the apical and basolateral compartment, supporting a role for apoM in sequestering molecules from secretion in urine. Transgenic overexpression of apoM in proximal tubular epithelial cells of mice did not protect against acute kidney injury.

scholarly journals Edaravone-Loaded Mesoscale Nanoparticles Treat Cisplatin-Induced Acute Kidney Injury

2020 ◽  
Author(s):  
Ryan M. Williams ◽  
Janki Shah ◽  
Elizabeth Mercer ◽  
Helen S. Tian ◽  
Justin M. Cheung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Co Morbidity ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Tumor Accumulation ◽  
Renal Proximal Tubular

AbstractCisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. In our prior work, we developed a highly-selective kidney-targeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

scholarly journals Linc-KIAA1737–2 promoted LPS-induced HK-2 cell apoptosis by regulating miR-27a-3p/TLR4/NF-κB axis

2021 ◽  
Author(s):  
Ming Hu ◽  
Jing Wei ◽  
Liu Yang ◽  
Jianhua Xu ◽  
Zhaofeng He ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Cell Apoptosis ◽  
Kidney Injury ◽  
Luciferase Assay ◽  
Tubular Epithelial Cells ◽  
Protein Levels ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Induced Apoptosis

AbstractInflammation and renal cell apoptosis participate in sepsis-induced acute kidney injury. Previous research found the upregulation of long non-coding RNA Linc-KIAA1737–2 in hypoxia- or inflammation-challenged human proximal tubular epithelial cells, but its role in sepsis-induced acute kidney injury is underexplored. In this research, we found that Linc-KIAA1737–2 could be upregulated in HK-2 human proximal tubular epithelial cells by LPS treatment, and knock-down of this lncRNA significantly attenuated LPS-induced apoptosis in HK-2 cells, while its overexpression showed opposite effect. MiR-27a-3p was confirmed to interact with Linc-KIAA1737–2 in HK-2 cells by RNA pull-down and dual-luciferase assay. MiR-27a-3p mimic transfection significantly attenuated LPS-induced HK-2 cell apoptosis by downregulating the protein levels of TLR4 and NF-κB, which was overturned by overexpression of Linc-KIAA1737–2. Our results suggested that Linc-KIAA1737–2 could promote LPS-induced apoptosis in HK-2 cells, and presumably sepsis-induced acute kidney injury, by regulating the miR-27a-3p/TLR4/NF-κB axis.

scholarly journals LincRNA-p21 Inhibits Cisplatin-Induced Apoptosis of Human Renal Proximal Tubular Epithelial Cells by Sponging miR-449a

2021 ◽  
pp. 1-7
Author(s):  
Zhen Li ◽  
Gang Hou
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Protective Role ◽  
Tubular Epithelial Cells ◽  
Breast Cancer Patients ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Induced Apoptosis

<b><i>Introduction:</i></b> LincRNA-p21 is predicted to interact with miR-449a, which plays a protective role in cisplatin-induced acute kidney injury (CIA). <b><i>Objective:</i></b> This study aimed to analyze the involvement of lincRNA-p21 in breast cancer patients with CIA. <b><i>Methods:</i></b> Levels of lincRNA-p21 in plasma from CIA, triple negative breast cancer, and control groups were measured by performing RT-qPCR. The potential interaction between lincRNA-p21 and miR-449a was first predicted by RT-qPCR. The relationship between lincRNA-p21 and miR-449a was analyzed by overexpression experiment. <b><i>Results:</i></b> We found that lincRNA-p21 is downregulated in CIA. Dual luciferase activity assay showed that lincRNA-p21 and miR-449a can interact with each other, while overexpression of lincRNA-p21 and miR-449a failed to affect the expression of each other. In human renal proximal tubular epithelial cells (HRPTEpCs), cisplatin led to the upregulated miR-449a but downregulated lincRNA-p21. Interestingly, lincRNA-p21 overexpression led to reduced enhancing effects of miR-449a on the cisplatin-induced apoptosis of HRPTEpCs. <b><i>Conclusion:</i></b> Therefore, lincRNA-p21 is downregulated in CIA and may sponge miR-449a to inhibit cisplatin-induced apoptosis of HRPTEpCs.

scholarly journals TCR+CD4−CD8− (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury

2020 ◽  
Vol 318 (6) ◽  
pp. F1500-F1512
Author(s):  
Jing Gong ◽  
Sanjeev Noel ◽  
Joshua Hsu ◽  
Errol L. Bush ◽  
Lois J. Arend ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Double Negative ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Induced Apoptosis

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4−CD8− double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

scholarly journals Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Proximal Tubular Epithelial Cells through miR-545-3p–TNFSF10

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1032
Author(s):  
Mei-Chuan Kuo ◽  
Wei-An Chang ◽  
Ling-Yu Wu ◽  
Yi-Chun Tsai ◽  
Ya-Ling Hsu
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Critical Process ◽  
Necrosis Factor

Hypoxia is regarded as one of the pathophysiologic mechanisms of kidney injury and further progression to kidney failure. Epithelial-to-mesenchymal transition (EMT) in kidney tubules is a critical process of kidney fibrosis. This study utilized transcriptome analysis to investigate hypoxia-induced EMT through microRNA (miRNA)-modulated EMT in proximal tubular epithelial cells (PTECs). RNA sequencing revealed eight miRNAs were upregulated and three miRNAs were downregulated in PTECs cultured under hypoxia compared with normoxia. Among the 11 miRNAs, miR-545-3p has the highest expression in PTECs exposed to hypoxia, and miR-545-3p suppressed tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10) expression. Hypoxia induced EMT in PTECs through miR-545-3p–TNFSF10 modulation, and TNFSF10-attenuated EMT resulted from hypoxia or miR-545-3p mimic transfection. These findings provided new perceptions of the unique regulation of the miR-545-3p–TNFSF10 interaction and their potential therapeutic effect in kidney injury induced by hypoxia.

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