scholarly journals Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Shaoqun Shu ◽  
Hui Wang ◽  
Jiefu Zhu ◽  
Zhiwen Liu ◽  
Danyi Yang ◽  
...  
Keyword(s):  
Er Stress ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Reciprocal Regulation ◽  
Tubular Cells ◽  
Chronic Kidney Injury ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells ◽  
Tgf Β1

AbstractBoth endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.

In vitro metabolism of 5-fluoro-2-glutathionyl-nitrobenzene by kidney proximal tubular cells studied by 19F-NMR

1995 ◽  
Vol 98 (2) ◽  
pp. 97-112 ◽  
Author(s):  
H.E.M.G. Haenen ◽  
I.M.C.M. Rietjens ◽  
J. Vervoort ◽  
J.H.M. Temmink ◽  
P.J. van Bladeren
Keyword(s):  
In Vitro Metabolism ◽  
19F Nmr ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells

scholarly journals The exosomes derived from urine of premature infants target MAPK8 via miR-30a-5p to protect cisplatin-induced acute kidney injury in mice

2021 ◽  
Author(s):  
Mingming Ma ◽  
Qiao Luo ◽  
Lijing Fan ◽  
Weilong Li ◽  
Qiang Li ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Premature Infants ◽  
Target Genes ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Hk2 Cells

Aim: Acute kidney injury (AKI), a global public health issue, not only causes millions of deaths every year, but is also a susceptible factor for chronic kidney disease (CKD). Nephrotoxic drugs are an important cause of AKI. There is still a lack of effective and satisfactory prevention method in clinical practice. This study investigated the protective effect of the exosomes derived from urine of premature infants on cisplatin-induced acute kidney injury. Methods: Isolation of exosomes from fresh urine of premature infants: The characteristics of exosomes were determined by flow cytometry, transmission electron microscopy and Western blotting. A C57BL/6 mice model of cisplatin-induced acute kidney injury was established. The mice in the experimental group were given 100ug exosomes dissolved in 200ul solution. The mice in the control group were given normal saline (200ul). These treatments were performed 24 hours after AKI was induced by intraperitoneal injection of cisplatin. To evaluate renal function, blood was drawn 24 hours after AKI model was established and serum creatinine (sCr) was measured. The mice were euthanized 72 hours after exosome treatment. The kidneys were collected for pathological examination, RNA and protein extraction, and the evaluation of renal tubular damage and apoptosis. In the in-vitro experiment, human renal cortex/proximal tubular cells (HK2) was induced by cisplatin to assess the protective ability of the exosomes derived from urine of premature infants. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blotting were used to evaluate the effect of exosomes treatment on the apoptosis of HK2 cells induced by cisplatin. Exosome microRNA sequencing technology and bioinformatics analysis method were applied to investigate the miRNAs enriched in exosomes and their target genes. The dual luciferase gene reporter system was used to detect the interaction of target genes. Results: Treatment of exosomes derived from urine of premature infants could decrease the level of serum creatinine and the apoptosis of renal tubular cell, inhibit the infiltration of inflammatory cell, protect mice from acute kidney injury induced by cisplatin and reduce mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes derived from urine of premature infants. It protected HK2 cells from cisplatin-induced apoptosis by targeting and down-regulating the 3'UTR of mitogen-activated protein kinases (MAPK8) mRNA. Conclusions: According to our results, the exosomes derived from urine of premature infants alleviated cisplatin-induced acute kidney injury in mice and inhibited the apoptosis of human proximal tubular cells (HK2) induced by cisplatin in vitro. MiR-30a-5p in exosomes inhibited cisplatin-induced MAPK activation, ameliorated apoptosis, and protected renal function. The exosomes derived from urine of premature infants provided a promising acellular therapy for AKI.

TDAG51 mediates epithelial-to-mesenchymal transition in human proximal tubular epithelium

2012 ◽  
Vol 303 (3) ◽  
pp. F467-F481 ◽  
Author(s):  
Rachel E. Carlisle ◽  
Alana Heffernan ◽  
Elise Brimble ◽  
Limin Liu ◽  
Danielle Jerome ◽  
...  
Keyword(s):  
Er Stress ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Tubular Epithelium ◽  
Proximal Tubular Cells ◽  
Mesenchymal Transition ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Proximal Tubular Epithelium ◽  
Tgf Β1

Epithelial-to-mesenchymal transition (EMT) contributes to renal fibrosis in chronic kidney disease. Endoplasmic reticulum (ER) stress, a feature of many forms of kidney disease, results from the accumulation of misfolded proteins in the ER and leads to the unfolded protein response (UPR). We hypothesized that ER stress mediates EMT in human renal proximal tubules. ER stress is induced by a variety of stressors differing in their mechanism of action, including tunicamycin, thapsigargin, and the calcineurin inhibitor cyclosporine A. These ER stressors increased the UPR markers GRP78, GRP94, and phospho-eIF2α in human proximal tubular cells. Thapsigargin and cyclosporine A also increased cytosolic Ca2+ concentration and T cell death-associated gene 51 (TDAG51) expression, whereas tunicamycin did not. Thapsigargin was also shown to increase levels of active transforming growth factor (TGF)-β1 in the media of cultured human proximal tubular cells. Thapsigargin induced cytoskeletal rearrangement, β-catenin nuclear translocation, and α-smooth muscle actin and vinculin expression in proximal tubular cells, indicating an EMT response. Subconfluent primary human proximal tubular cells were induced to undergo EMT by TGF-β1 treatment. In contrast, tunicamycin treatment did not produce an EMT response. Plasmid-mediated overexpression of TDAG51 resulted in cell shape change and β-catenin nuclear translocation. These results allowed us to develop a two-hit model of ER stress-induced EMT, where Ca2+ dysregulation-mediated TDAG51 upregulation primes the cell for mesenchymal transformation via Wnt signaling and then TGF-β1 activation leads to a complete EMT response. Thus the release of Ca2+ from ER stores mediates EMT in human proximal tubular epithelium via the induction of TDAG51.

scholarly journals miR-214 represses mitofusin-2 to promote renal tubular apoptosis in ischemic acute kidney injury

2020 ◽  
Vol 318 (4) ◽  
pp. F878-F887 ◽  
Author(s):  
Yu Yan ◽  
Zhengwei Ma ◽  
Jiefu Zhu ◽  
Mengru Zeng ◽  
Hong Liu ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Kidney Injury ◽  
Atp Depletion ◽  
Mitochondrial Fragmentation ◽  
Proximal Tubular Cells ◽  
Mitofusin 2 ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Kidney Proximal Tubular Cells

Disruption of mitochondrial dynamics is an important pathogenic event in both acute and chronic kidney diseases, but the underlying mechanism remains poorly understood. Here, we report the regulation of mitofusin-2 (Mfn2; a key mitochondrial fusion protein) by microRNA-214 (miR-214) in renal ischemia-reperfusion that contributes to mitochondrial fragmentation, renal tubular cell death, and ischemic acute kidney injury (AKI). miR-214 was induced, whereas Mfn2 expression was decreased, in mouse ischemic AKI and cultured rat kidney proximal tubular cells (RPTCs) following ATP depletion treatment. Overexpression of miR-214 decreased Mfn2. Conversely, inhibition of miR-214 with anti-miR-214 prevented Mfn2 downregulation in RPTCs following ATP depletion. Anti-miR-214 further ameliorated mitochondrial fragmentation and apoptosis, whereas overexpression of miR-214 increased apoptosis, in ATP-depleted RPTCs. To test regulation in vivo, we established a mouse model with miR-214 specifically deleted from kidney proximal tubular cells (PT- miR-214−/−). Compared with wild-type mice, PT- miR-214−/− mice had less severe tissue damage, fewer apoptotic cells, and better renal function after ischemic AKI. miR-214 induction in ischemic AKI was suppressed in PT- miR-214−/− mice, accompanied by partial preservation of Mfn2 in kidneys. These results unveil the miR-214/Mfn2 axis that contributes to the disruption of mitochondrial dynamics and tubular cell death in ischemic AKI, offering new therapeutic targets.

scholarly journals Nephrotoxicity Of Polymyxin B: Experimental Study In Cells And Implications For Nursing Practice

2014 ◽  
Vol 48 (2) ◽  
pp. 272-277 ◽  
Author(s):  
Luciana Barros de Moura Neiva ◽  
Fernanda Teixeira Borges ◽  
Mirian Watanabe ◽  
Edson de Andrade Pessoa ◽  
Dulce Aparecida Barbosa ◽  
...  
Keyword(s):  
Fluorescent Dyes ◽  
Cell Damage ◽  
Kidney Injury ◽  
In Vitro Study ◽  
Polymyxin B ◽  
Concentration Cell ◽  
Tubular Cells ◽  
Risk Patients ◽  
Proximal Tubular

The aim of the study was to characterize the cell damage mechanisms involved in the pathophysiology of cytotoxicity of polymyxin B in proximal tubular cells (LLC - PK1) and discuss about the nurses interventions to identify at risk patients and consider prevention or treatment of nephrotoxicity acute kidney injury. This is a quantitative experimental in vitro study, in which the cells were exposed to 375μM polymyxin B sulfate concentration. Cell viability was determined by exclusion of fluorescent dyes and morphological method with visualization of apoptotic bodies for fluorescence microscopy. Cells exposed to polymyxin B showed reduced viability, increased number of apoptotic cells and a higher concentration of the enzyme lactate dehydrogenase. The administration of polymyxin B in vitro showed the need for actions to minimize adverse effects such as nephrotoxicity.


Sign in / Sign up

Export Citation Format

Share Document