scholarly journals microRNA in Extracellular Vesicles Released by Damaged Podocytes Promote Apoptosis of Renal Tubular Epithelial Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1409 ◽  
Author(s):  
Jin Seok Jeon ◽  
Eunbit Kim ◽  
Yun-Ui Bae ◽  
Won Mi Yang ◽  
Haekyung Lee ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Extracellular Vesicles ◽  
Cell Damage ◽  
Tubular Epithelial Cell ◽  
Glomerular Disease ◽  
Sequencing Analysis ◽  
Tubular Epithelial Cells ◽  
Tubular Injury ◽  
Healthy Human ◽  
Hk2 Cells

Tubular injury and fibrosis are associated with progressive kidney dysfunction in advanced glomerular disease. Glomerulotubular crosstalk is thought to contribute to tubular injury. microRNAs (miRNAs) in extracellular vesicles (EVs) can modulate distant cells. We hypothesized that miRNAs in EVs derived from injured podocytes lead to tubular epithelial cell damage. As proof of this concept, tubular epithelial (HK2) cells were cultured with exosomes from puromycin-treated or healthy human podocytes, and damage was assessed. Sequencing analysis revealed the miRNA repertoire of podocyte EVs. RNA sequencing identified 63 upregulated miRNAs in EVs from puromycin-treated podocytes. Among them, five miRNAs (miR-149, -424, -542, -582, and -874) were selected as candidates for inducing tubular apoptosis according to a literature-based search. To validate the effect of the miRNAs, HK2 cells were treated with miRNA mimics. EVs from injured podocytes induced apoptosis and p38 phosphorylation of HK2 cells. The miRNA-424 and 149 mimics led to apoptosis of HK2 cells. These results show that miRNAs in EVs from injured podocytes lead to damage to tubular epithelial cells, which may contribute to the development of tubular injury in glomerular disease.

Intranuclear Crystals in Regenerating Canine Kidneys

1973 ◽  
Vol 31 ◽  
pp. 412-413
Author(s):  
D.G. Osborne ◽  
L.J. McCormack ◽  
M.O. Magnusson ◽  
W.S. Kiser
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Tubular Epithelial Cell ◽  
Tubular Epithelial Cells ◽  
Cell Nuclei ◽  
Crystalline Structures ◽  
Small Crystals ◽  
Membrane Bound

During a project in which regenerative changes were studied in autotransplanted canine kidneys, intranuclear crystals were seen in a small number of tubular epithelial cells. These crystalline structures were seen in the control specimens and also in regenerating specimens; the main differences being in size and number of them. The control specimens showed a few tubular epithelial cell nuclei almost completely occupied by large crystals that were not membrane bound. Subsequent follow-up biopsies of the same kidneys contained similar intranuclear crystals but of a much smaller size. Some of these nuclei contained several small crystals. The small crystals occurred at one week following transplantation and were seen even four weeks following transplantation. As time passed, the small crystals appeared to fuse to form larger crystals.

MO328ASYMPTOMATIC HYPERURICEMIA ACTS AS ANTIOXIDANT DURING ACUTE KIDNEY INJURY AND DISEASE*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Qiuyue Ma ◽  
Viviane Gnemmi ◽  
Anders Hans-Joachim ◽  
Stefanie Steiger
Keyword(s):  
Acute Kidney Injury ◽  
Fatty Acid ◽  
Epithelial Cells ◽  
Kidney Function ◽  
Metabolic Activity ◽  
Mitochondrial Biogenesis ◽  
Kidney Injury ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Tubular Injury

Abstract Background and Aims Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells. Method Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry. Results We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right). Conclusion Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.

scholarly journals CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Antoine Dewitte ◽  
Julien Villeneuve ◽  
Sébastien Lepreux ◽  
Marion Bouchecareilh ◽  
Xavier Gauthereau ◽  
...  
Keyword(s):  
Blood Platelets ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Hypoxic Stress ◽  
Tubular Epithelium ◽  
Tubular Epithelial Cells ◽  
Tubular Injury ◽  
Short Term ◽  
Inflammatory Agent ◽  
Hypoxic Conditions

Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.

scholarly journals Expression of Fas and Fas Ligand on Mouse Renal Tubular Epithelial Cells in the Generalized Shwartzman Reaction and Its Relationship to Apoptosis

1999 ◽  
Vol 67 (8) ◽  
pp. 4112-4118 ◽  
Author(s):  
Naoki Koide ◽  
Kayo Narita ◽  
Yutaka Kato ◽  
Tsuyoshi Sugiyama ◽  
Dipshikha Chakravortty ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Fas Ligand ◽  
Cell Injury ◽  
Tubular Epithelial Cell ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cell ◽  
Renal Tubular ◽  
Epithelial Cell Injury

ABSTRACT Previously we reported that the consecutive injection of lipopolysaccharide (LPS) into LPS-sensitized mice for the generalized Shwartzman reaction (GSR) appeared to induce the injury of renal tubular epithelial cells via apoptosis. The aim of this study was to characterize the mechanism of renal tubular epithelial cell injury in GSR. The expression of Fas and Fas ligand was immunohistochemically detected on renal tubular epithelial cells from GSR-induced mice, although neither Fas nor Fas ligand was found in cells from untreated control mice or in cells from mice receiving a single injection of LPS. GSR-induced renal tubular epithelial cell injury was produced in neither Fas-negative MRL-lpr/lpr mice nor Fas ligand-negative MRL-gld/gld mice. The administration of anti-gamma interferon antibody together with a preparative injection of LPS prevented the expression of Fas and Fas ligand and the apoptosis of renal tubular epithelial cells. A provocative injection of tumor necrosis factor alpha into LPS-sensitized mice augmented Fas and Fas ligand expression and the apoptosis of renal tubular epithelial cells. The administration of tumor necrosis factor alpha to interleukin-12-sensitized mice resulted in Fas and Fas ligand expression and the apoptosis. Sensitization with interleukin-12 together with anti-gamma interferon antibody did not cause the apoptosis of renal tubular epithelial cells. It was suggested that the Fas/Fas ligand system probably plays a critical role in the development of renal tubular epithelial cell injury through apoptotic cell death.

Clostridium perfringens epsilon toxin is cytotoxic for human renal tubular epithelial cells

2010 ◽  
Vol 30 (4) ◽  
pp. 275-282 ◽  
Author(s):  
Mariano E. Fernandez Miyakawa ◽  
Osvaldo Zabal ◽  
Claudia Silberstein
Keyword(s):  
Epithelial Cells ◽  
Clostridium Perfringens ◽  
Cell Model ◽  
Cell Damage ◽  
Primary Cultures ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Epsilon Toxin ◽  
Renal Tubular

Clostridium perfringens epsilon toxin (ETX) is responsible for a fatal enterotoxemia in different animal species, producing extensive renal damage, neurological disturbance and edema of lungs, heart and kidneys. However, there is no information about the susceptibility of humans to ETX. Here, we report that primary cultures of human renal tubular epithelial cells (HRTEC) exposed to ETX showed a marked swelling with subsequent large blebs surrounding most cells. The incubation of HRTEC with ETX produced a reduction of cell viability in a dose- and time-dependent manner. The CD50 after 1-hour and 24-hour incubation were 3 µg/mL and 0.5 µg/mL, respectively. The pulse with ETX for 3 min was enough to produce a significant cytotoxic effect on HRTEC after 1-hour incubation. ETX binds to HRTEC forming a large complex of about 160 kDa similar to what was found in the Madin-Darby canine kidney (MDCK) cell line. The HRTEC could be a useful cell model to improve the understanding of the mechanisms involved on the cell damage mediated by ETX.

Proteinuria as a determinant of renal expression of heme oxygenase-1: studies in models of glomerular and tubular proteinuria in the rat

2006 ◽  
Vol 290 (1) ◽  
pp. F196-F204 ◽  
Author(s):  
José Pedraza-Chaverri ◽  
Narayana S. Murali ◽  
Anthony J. Croatt ◽  
Jawed Alam ◽  
Joseph P. Grande ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Tubular Epithelial Cells ◽  
Tubular Injury ◽  
Tubular Proteinuria ◽  
Glomerular Proteinuria ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Diseased Kidney

Heme oxygenase-1 (HO-1), a cytoprotective gene, is commonly induced in renal tubules in the diseased kidney. Because proteinuria is a hallmark for kidney disease, we examined the relationship between proteinuria and tubular induction of HO-1, specifically questioning whether increased trafficking of protein across the renal tubular epithelium, as a consequence of proteinuria, induces tubular expression of HO-1. We examined a model of glomerular proteinuria induced by daily injections of BSA, which is associated with increased tubular uptake of filtered protein, and a model of tubular proteinuria induced by maleate, the latter exhibiting decreased tubular uptake and trafficking of protein. The BSA model of glomerular proteinuria failed to exhibit induction of HO-1; HO-1 was not induced in proximal tubular epithelial cells exposed to BSA. In contrast, in maleate nephropathy wherein tubular uptake of protein is decreased because of generalized proximal tubular injury induced by maleate, HO-1 was strongly induced in proximal tubules; inhibition of HO activity in maleate nephropathy worsened proteinuria, renal histological injury, and apoptosis. In renal proximal tubular epithelial cells, maleate induced HO-1 and caused apoptosis, the latter increased when HO activity was inhibited. From these studies, we conclude that expression of HO-1 in the diseased kidney cannot be ascribed to the tubular uptake and metabolism of protein such as albumin, and that the expression of HO-1 in a model of tubular proteinuria reflects a functionally significant stress response to toxin-induced proximal tubular injury.

scholarly journals Caspase-11 promotes cisplatin-induced renal tubular apoptosis through a caspase-3-dependent pathway

2018 ◽  
Vol 314 (2) ◽  
pp. F269-F279 ◽  
Author(s):  
Naijun Miao ◽  
Bao Wang ◽  
Dan Xu ◽  
Yanzhe Wang ◽  
Xinxin Gan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Tubular Epithelial Cells ◽  
Tubular Injury ◽  
Renal Tubular Epithelial Cells ◽  
Small Interference Rna ◽  
Fluorescence Confocal Microscopy ◽  
Renal Tubular ◽  
Interference Rna

Renal tubular injury is the hallmark of cisplatin-induced nephrotoxicity. Caspase-11, a member of the caspase family, plays an important role in inflammation and cell death. However, its role in cisplatin-induced renal tubular injury remains unclear. In cisplatin-treated mice, caspase-11 expression was significantly elevated and the expression of caspase-11 was mainly located in renal tubule. Inhibition of caspase-11 by small-interference RNA or its inhibitor wedelolactone attenuated cisplatin-induced renal dysfunction and tubular injury. In cultured primary renal tubular epithelial cells, cisplatin significantly promoted the expression and activation of caspase-11. Inhibition of caspase-11 by small-interference RNA reduced cisplatin-induced cell apoptosis. Overexpression of caspase-11 promoted cell apoptosis by activating the caspase-3-related cell apoptosis. Furthermore, coimmunoprecipitation results showed there was a direct interaction between caspase-11 and caspase-3, and the interaction was enhanced by cisplatin. The fluorescence confocal microscopy results showed that caspase-11 and caspase-3 were colocalized in the cytoplasm of renal tubular epithelial cells. These results demonstrate that caspase-11 plays an important role in cisplatin-induced renal tubular injury. Caspase-11 promotes renal epithelial cell apoptosis by activating the caspase-3-dependent apoptotic pathway. Caspase-11 might be a potential target for therapeutic treatment against cisplatin-induced nephrotoxicity.

scholarly journals Tubule-specific protein nanocages potentiate targeted renal fibrosis therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xuan Zhang ◽  
Qian Chen ◽  
Liyuan Zhang ◽  
Haiping Zheng ◽  
Chunjie Lin ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Core Protein ◽  
Tubular Epithelial Cell ◽  
Specific Protein ◽  
Modern Medicine ◽  
Systemic Toxicity ◽  
Tubular Epithelial Cells ◽  
Sequencing Data ◽  
Loop Region

Abstract Background Despite the dramatic advances in modern medicine, efficient therapeutic measures for renal fibrosis remain limited. Celastrol (CLT) is effective in treating renal fibrosis in rat models, while causing severe systemic toxicity. Thus, we designed a tubule-specific nanocage (K3-HBc NCs) that effectively deliver CLT to tubular epithelial cell in a virus-like manner. The targeting ligand (K3) to tubular epithelial cells was displayed on the surface of Hepatitis B core protein (HBc) NCs by genetic fusion to the major immunodominant loop region. Ultra-small CLT nanodots were subtly encapsulated into the cavity through electrostatic interaction with the disassembly and reassembly of K3-HBc NCs, to yield K3-HBc/CLT complex. The efficacy of K3-HBc/CLT NCs were demonstrated in Unilateral ureteral obstruction (UUO)-induced renal fibrosis. Results The self-assembled K3-HBc/CLT could specifically target tubular epithelial cells via affinity with K3 ligand binding to the megalin receptor, significantly attenuating renal fibrosis. Remarkably, K3-HBc/CLT NCs significantly increased therapeutic efficacy and reduced the systemic toxicity in comparison with free CLT in UUO-induced mouse renal fibrosis model. Importantly, analysis of RNA sequencing data suggested that the anti-fibrotic effect of K3-HBc/CLT could be attributed to suppression of premature senescence in tubular epithelial cells via p21Cip1 and p16Ink4a pathway. Conclusion The tubule-specific K3-HBc/CLT represented a promising option to realize precise treatment for renal fibrosis.

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