scholarly journals Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation

2018 ◽  
Vol 29 (3) ◽  
pp. 919-935 ◽  
Author(s):  
Lin-Li Lv ◽  
Ye Feng ◽  
Yi Wen ◽  
Wei-Jun Wu ◽  
Hai-Feng Ni ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Cell ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Tail Vein Injection ◽  
Chronic Kidney Injury ◽  
Ccl2 Mrna ◽  
Injury Models ◽  
Tubulointerstitial Inflammation

Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. In vitro stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.

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 Caspase-11 Mediates Pyroptosis of Tubular Epithelial Cells and Septic Acute Kidney Injury

2019 ◽  
Vol 44 (4) ◽  
pp. 465-478 ◽  
Author(s):  
Zhiming Ye ◽  
Li Zhang ◽  
Ruizhao Li ◽  
Wei Dong ◽  
Shuangxin Liu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cells ◽  
Serum Creatinine ◽  
Protein Expression ◽  
Kidney Injury ◽  
Interleukin 1Β ◽  
Tubular Epithelial Cells

Background/Aims: Acute kidney injury (AKI) is a serious complication of sepsis and has a high morbidity and mortality rate. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock, but its role in tubular epithelial cell death and whether it contributes to sepsis-associated AKI remains unknown. Methods: The caspase-11–/– mouse received an intraperitoneal injection of lipopolysaccharide (LPS, 40 mg/kg body weight). Caspase-11–/– renal tubular epithelial cells (RTECs) form C57BL caspase-11–/– mice were treated with LPS in vitro. The IL-1β ELISA kit and Scr assay kit were used to measure the level of interleukin-1β and serum creatinine. Annexin V-FITC assay and TUNEL staining assay were used to detect the cell death in different groups in vitro and in vivo. Western blot was performed to analyze the protein expression of caspase-11 and Gsdmdc1. Results: LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. However, the increase in pyroptosis-related protein expression induced by LPS was attenuated with caspase-11 knockout, both in vitro and in vivo. Furthermore, when challenged with lethal doses of systemic LPS, pathologic abnormalities in renal structure, increased serum and kidney interleukin-1β, increased serum creatinine, and animal death were observed in wild-type mice but prevented in caspase-11–/– mice. Conclusions: Caspase-11-induced pyroptosis of RTECs is a key event during septic AKI, and targeting of caspase-11 in RTECs may serve as a novel therapeutic target in septic AKI.

Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration

2019 ◽  
Vol 34 (10) ◽  
pp. 1669-1680 ◽  
Author(s):  
Takamasa Iwakura ◽  
Zhibo Zhao ◽  
Julian A Marschner ◽  
Satish Kumar Devarapu ◽  
Hideo Yasuda ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Function ◽  
Mtt Assay ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Dipeptidyl Peptidase 4 ◽  
Cxc Chemokine

AbstractBackgroundCisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.MethodsIn in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.ResultsIn in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.ConclusionsThe DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.

scholarly journals Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Timo N. Haschler ◽  
Harry Horsley ◽  
Monika Balys ◽  
Glenn Anderson ◽  
Jan-Willem Taanman ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mitochondrial Function ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Atp Production ◽  
Form And Function ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

AbstractIschemia is a major cause of kidney damage. Proximal tubular epithelial cells (PTECs) are highly susceptible to ischemic insults that frequently cause acute kidney injury (AKI), a potentially life-threatening condition with high mortality. Accumulating evidence has identified altered mitochondrial function as a central pathologic feature of AKI. The mitochondrial NAD+-dependent enzyme sirtuin 5 (SIRT5) is a key regulator of mitochondrial form and function, but its role in ischemic renal injury (IRI) is unknown. SIRT5 expression was increased in murine PTECs after IRI in vivo and in human PTECs (hPTECs) exposed to an oxygen/nutrient deprivation (OND) model of IRI in vitro. SIRT5-depletion impaired ATP production, reduced mitochondrial membrane potential, and provoked mitochondrial fragmentation in hPTECs. Moreover, SIRT5 RNAi exacerbated OND-induced mitochondrial bioenergetic dysfunction and swelling, and increased degradation by mitophagy. These findings suggest SIRT5 is required for normal mitochondrial function in hPTECs and indicate a potentially important role for the enzyme in the regulation of mitochondrial biology in ischemia.

scholarly journals ING2 Controls Mitochondrial Respiration via Modulating MRPL12 Ubiquitination in Renal Tubular Epithelial Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Ying Yang ◽  
Chensheng Li ◽  
Xia Gu ◽  
Junhui Zhen ◽  
Suwei Zhu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mitochondrial Respiration ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Mitochondrial Injury ◽  
Mitochondrial Transcription Factor ◽  
Mtdna Transcription

Mitochondrial injury of tubular epithelial cells (TECs) is the key pathogenic event underlying various kidney diseases and a potential intervening target as well. Our previous study demonstrated that ING2 is ubiquitously expressed at tubulointerstitial area within kidneys, while its role in regulating TEC mitochondrial respiration is not fully elucidated. To clarify the roles of ING2 in mitochondrial homeostasis of TECs and pathogenesis of acute ischemic kidney injury, Western blot, PCR, immunofluorescence, immunoprecipitation, and oxygen consumption rate assay were applied to address the roles of ING2 in modulating mitochondrial respiration. We further complemented these studies with acute ischemic kidney injury both in vitro and in vivo. In vitro study demonstrated ING2 could positively control TEC mitochondrial respiration. Concurrently, both mRNA and protein levels of mtDNA encoded respiratory chain components were altered by ING2, suggesting ING2 could regulate mtDNA transcription. In mechanism, ING2 could regulate the ubiquitination of a newly identified mitochondrial transcription factor MRPL12, thereby modulating its cellular stability and abundance. We also demonstrated ING2-mediated modulation on mtDNA transcription and mitochondrial respiration are involved in serum deprivation induced TEC injuries. Finally, immunohistochemistry study revealed that ING2 expression was significantly altered in kidney biopsies with acute ischemic kidney injury. In vivo study suggested that kidney specific ING2 overexpression could effectively ameliorate acute ischemic kidney injury. Our study demonstrated that ING2 is a crucial modulator of TEC mitochondrial respiration. These findings suggested a unrecognized role of ING2 in TEC mitochondrial energetic homeostasis and a potential intervening target for TEC mitochondrial injury associated pathologies.

MicroRNA-34a Suppresses Autophagy in Tubular Epithelial Cells in Acute Kidney Injury

2015 ◽  
Vol 42 (2) ◽  
pp. 168-175 ◽  
Author(s):  
Xiu-Juan Liu ◽  
Quan Hong ◽  
Zhen Wang ◽  
Yan-Yan Yu ◽  
Xin Zou ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Autophagic Activity ◽  
The Relationship ◽  
Vitro Data ◽  
In Vitro Data

Background: Acute kidney injury (AKI) is traditionally described as a condition leading to rapid damage to kidney function, eventually becoming a significant healthcare concern with a high mortality rate. Autophagy deficiency in the tubular epithelial cells is the main cause of AKI; however, the underlying molecular mechanism remains to be defined. MicroRNAs (miRNAs) are related to autophagy in many diseases. This study was aimed at investigating the relationship between miRNA expression and autophagic activity in the pathogenesis of AKI. Methods: A mouse model of AKI was produced by ischemia reperfusion (I/R). The expressions of microRNA-34a (miR-34a) and the autophagy-related protein LC3 II/I and p62 were determined in renal tissues and the tubular epithelial cells (RTECs). Moreover, the autophagic activity was investigated after miR-34a overexpression and inhibition. Additionally, the effect of miR-34a on its target gene in regulating autophagic activity in RTECs was also investigated. Results: I/R suppressed the autophagic activity and increased the expression of miR-34a in renal tissues. The in vitro data showed that the upregulation of miR-34a suppressed, whereas the inhibition of miR-34a promoted, autophagy in RTECs. Moreover, miR-34a could directly bind to Atg4B 3′-untranslated region. In addition, the knockdown of Atg4B expression inhibited the autophagic activity in RTECs. Conclusion: This study indicated that miR-34a might regulate the autophagic activity and can cause injury in I/R RTECs via targeting Atg4B.

scholarly journals PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Dou ◽  
Hang Tong ◽  
Yichun Yang ◽  
Han Zhang ◽  
Hua Gan
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Induced Apoptosis

We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.

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