scholarly journals The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

2021 ◽  
Vol 8 ◽  
Author(s):  
Chao Li ◽  
Wei Wang ◽  
Shuai-shuai Xie ◽  
Wen-xian Ma ◽  
Qian-wen Fan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Epithelial Cells ◽  
Programmed Cell Death ◽  
Vascular Endothelial Cells ◽  
Epigenetic Modification ◽  
Kidney Injury ◽  
Cell Types ◽  
Acute Injury ◽  
Tubular Epithelial Cells

Sepsis is a systemic inflammatory response syndrome caused by infection, following with acute injury to multiple organs. Sepsis-induced acute kidney injury (AKI) is currently recognized as one of the most severe complications related to sepsis. The pathophysiology of sepsis-AKI involves multiple cell types, including macrophages, vascular endothelial cells (ECs) and renal tubular epithelial cells (TECs), etc. More significantly, programmed cell death including apoptosis, necroptosis and pyroptosis could be triggered by sepsis in these types of cells, which enhances AKI progress. Moreover, the cross-talk and connections between these cells and cell death are critical for better understanding the pathophysiological basis of sepsis-AKI. Mitochondria dysfunction and oxidative stress are traditionally considered as the leading triggers of programmed cell death. Recent findings also highlight that autophagy, mitochondria quality control and epigenetic modification, which interact with programmed cell death, participate in the damage process in sepsis-AKI. The insightful understanding of the programmed cell death in sepsis-AKI could facilitate the development of effective treatment, as well as preventive methods.

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 Cell Death Patterns Due to Warm Ischemia or Reperfusion in Renal Tubular Epithelial Cells Originating from Human, Mouse, or the Native Hibernator Hamster

Biology ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 48 ◽  
Author(s):  
Theodoros Eleftheriadis ◽  
Georgios Pissas ◽  
Georgia Antoniadi ◽  
Vassilios Liakopoulos ◽  
Ioannis Stefanidis
Keyword(s):  
Lipid Peroxidation ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Human Cells ◽  
Tubular Epithelial Cells

Ischemia–reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia–reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia–reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end-point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia–reperfusion-induced acute kidney injury in humans.

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.

Macrophages induce apoptosis in normal cells in vivo

Development ◽  
1997 ◽  
Vol 124 (18) ◽  
pp. 3633-3638 ◽  
Author(s):  
G. Diez-Roux ◽  
R.A. Lang
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Direct Evidence ◽  
Vascular Endothelial Cells ◽  
Target Cells ◽  
Vascular Endothelial ◽  
Normal Cells ◽  
Apoptotic Morphology

It is well established that macrophages have a function in scavenging apoptotic bodies from cells undergoing programmed cell death. Here we show that macrophages can also induce apoptosis of normal cells. Using injected toxic liposomes to eliminate macrophages in the anterior chamber of the rat eye, we provide direct evidence that, in vivo, macrophages induce apoptosis in normal vascular endothelial cells during programmed capillary regression. Macrophage elimination resulted in the survival of endothelial cells that normally would die and the persistence of functional capillaries. Furthermore, replacement of eliminated macrophages with bone-marrow-derived macrophages ‘rescued’ lack of capillary regression. Viability of the persistent target cells was demonstrated through their lack of apoptotic morphology, expression of intracellular esterases and synthesis of DNA. These results uncover a new function for macrophages in the remodeling of tissues through the induction of programmed cell death and provide direct evidence of a key role for macrophages in capillary regression.

scholarly journals Extracellular 2′,3′-cAMP and 3′,5′-cAMP stimulate proliferation of preglomerular vascular endothelial cells and renal epithelial cells

2012 ◽  
Vol 303 (7) ◽  
pp. F954-F962 ◽  
Author(s):  
Edwin K. Jackson ◽  
Delbert G. Gillespie
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Cells ◽  
Extracellular Adenosine ◽  
Tubular Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Kidneys release into the extracellular compartment 3′,5′-cAMP and its positional isomer 2′,3′-cAMP. The purpose of the present study was to investigate the metabolism of extracellular 2′,3′-cAMP and 3′,5′-cAMP in preglomular vascular endothelial and proximal tubular epithelial cells and to determine whether these cAMPs and their downstream metabolites affect cellular proliferation. In preglomerular vascular endothelial and proximal tubular epithelial cells, 1) extracellular 2′,3′-cAMP increased extracellular levels of 3′-AMP and 2′-AMP, whereas extracellular 3′,5′-cAMP increased extracellular levels of 5′-AMP; 2) extracellular 5′-AMP, 3′-AMP, and 2′-AMP increased extracellular adenosine; 3) α,β-methylene-adenosine-5′-diphosphate (CD73 inhibitor) prevented the 5′-AMP-induced increase in extracellular adenosine in preglomerular vascular endothelial cells, but did not affect the 5′-AMP-induced increase in extracellular adenosine in proximal tubular cells or the 3′-AMP-induced or 2′-AMP-induced increase in extracellular adenosine in either cell type; 4) extracellular 2′,3′-cAMP, 3′-AMP, 2′-AMP, 3′,5′-cAMP, 5′-AMP, and adenosine stimulated proliferation of both preglomerular vascular endothelial and proximal tubular cells; and 5) MRS-1754 (selective A2B receptor antagonist) abolished the progrowth effects of extracellular 2′,3′-cAMP, 3′-AMP, 2′-AMP, 3′,5′-cAMP, 5′-AMP, and adenosine in both cell types. Extracellular 2′,3′-cAMP and 3′,5′-cAMP stimulate proliferation of preglomerular vascular endothelial cells and proximal tubular cells. The mechanism by which the cAMPs increase cell proliferation entails 1) metabolism to their respective AMPs, 2) metabolism of their respective AMPs to adenosine (which for 5′-AMP in preglomerular vascular endothelial cells is mediated by CD73), and 3) activation of A2B receptors. Both extracellular 2′,3′-cAMP and 3′,5′-cAMP may help restore architecture of the preglomerular microcirculation and tubular system following kidney injury.

Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses

2001 ◽  
Vol 280 (3) ◽  
pp. H1293-H1300 ◽  
Author(s):  
Muriel Vayssier-Taussat ◽  
Tura Camilli ◽  
Yolande Aron ◽  
Catherine Meplan ◽  
Pierre Hainaut ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Tobacco Smoke ◽  
Stress Responses ◽  
Stress Proteins ◽  
Vascular Endothelial Cells ◽  
Cell Types ◽  
Heme Oxygenase 1 ◽  
Vascular Endothelial ◽  
Contrast Exposure

Smoking is an important risk factor for atherosclerosis. We compared tobacco smoke filtrate with benzo[ a]pyrene (a prominent xenobiotic component of tobacco smoke) for the capacity to induce stress proteins and cause cell death in human monocytes and vascular endothelial cells, two cell types that are involved in the formation of atherosclerotic lesions. Exposure to freshly prepared filtrates of tobacco smoke induced in both monocytes and endothelial cells expression of the inducible heat shock protein (HSP)70 and heme oxygenase-1 (HO-1) and produced loss of mitochondrial membrane potential. Later, cell death by apoptosis or necrosis occurred depending on the concentration of tobacco smoke. These toxic effects could be prevented by the antioxidant N-acetylcysteine. In contrast, exposure of these cells to benzo[ a]pyrene alone evoked neither stress proteins nor mitochondrial damage but did induce cell death by necrosis. Thus our results indicate that tobacco smoke rapidly induces complex oxidant-mediated stress responses in both vascular endothelial cells and circulating monocytes that are independent of the benzo[ a]pyrene content of the smoke.

scholarly journals Tubule-derived lactate is required for fibroblast activation in acute kidney injury

2020 ◽  
Vol 318 (3) ◽  
pp. F689-F701
Author(s):  
Yan Shen ◽  
Lei Jiang ◽  
Ping Wen ◽  
Yinyin Ye ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Epithelial Cells ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Kidney Injury ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Fibroblast Activation ◽  
Matrix Deposition

Acute kidney injury (AKI) is a highly prevalent medical syndrome associated with high mortality and morbidity. Several types of cells, including epithelial cells, vascular endothelial cells, pericytes, and macrophages, participate in the development of AKI. Recently, renal fibroblasts were found to play an important role in the regulation of tubular injury, repair, and recovery after AKI. However, the mechanisms underlying fibroblast activation and proliferation during the progression of AKI remain unclear. In the present study, we found many activated myofibroblasts located in the renal interstitium with an abundance of extracellular matrix deposition following folic acid-induced AKI. The proliferative pattern of tubular epithelial cells and interstitial cells following acute injury was different, indicating that the proliferation of fibroblasts followed the proliferation of tubular epithelial cells. Furthermore, we observed that proliferative tubular epithelial cells preferred aerobic glycolysis as the dominating metabolic pathway in the progression of AKI. Lactate generated from injured tubules was taken up by interstitial fibroblasts in the later stages of AKI, which induced fibroblast activation and proliferation in vitro. Early inhibition of lactate production in tubules by glycolytic inhibitors suppressed fibroblast activation after folic acid-induced injury. Collectively, these results support the important role of fibroblasts in the development of AKI and suggest that lactate produced by glycolysis in tubular epithelial cells is a novel regulator of fibroblast activation and proliferation.

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