Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs

Łoboda, Agnieszka; Mucha, Olga; Podkalicka, Paulina; Sobczak, Mateusz; Miksza-Cybulska, Anna; Kaczara, Patrycja; Józkowicz, Alicja; Dulak, Józef

doi:10.18388/abp.2018_2658

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…The mechanism might be related to HO-1 and downstream NF-E2related factor 2 translocation to the nucleus and its effect on gene expression [58][59][60][61] . A study by Loboda et al 62 showed that cyclosporine A decreased the expression of miR-200b significantly in Ho-1 (−/−) proximal tubular epithelial cells. By detecting the level of miR-200b in BMMSC cells and exosomes stimulated by TNF-α and HO-1 modification, we found that the expression level of miR-200b in BMMSCs with both HO-1 modification and TNF-α stimulation was significantly higher than that after single factor stimulation and in unstimulated BMMSCs.…”

Section: Discussionmentioning

confidence: 99%

MiR-200b in heme oxygenase-1-modified bone marrow mesenchymal stem cell-derived exosomes alleviates inflammatory injury of intestinal epithelial cells by targeting high mobility group box 3

et al. 2020

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Heme Oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) are effective to protect and repair transplanted small bowel and intestinal epithelial cells (IECs); however, the mechanism and the role of HO-1/BMMSCs-derived exosomes is unclear. In the present study, we aimed to verify that exosomes from a HO-1/BMMSCs and IEC-6 cells (IEC-6s) co-culture system could reduce the apoptosis of IEC-6s and decrease the expression of the tight junction protein, zona occludens 1, in the inflammatory environment. Using mass spectrometry, we revealed that high mobility group box 3 (HMGB3) and phosphorylated c-Jun NH2-terminal kinase (JNK), under the influence of differentially abundant proteins identified through proteomic analysis, play critical roles in the mechanism. Further studies indicated that microRNA miR-200b, which was upregulated in exosomes derived from the co-culture of HO-1/BMMSCs and IEC-6s, exerted its role by targeting the 3′ untranslated region of Hmgb3 in this biological process. Functional experiments confirmed that miR-200b overexpression could reduce the inflammatory injury of IEC-6s, while intracellular miR-200b knockdown could significantly block the protective effect of HO-1/BMMSCs exosomes on the inflammatory injury of IEC-6s. In addition, the level of miR-200b in cells and exosomes derived from HO-1/BMMSCs stimulated by tumor necrosis factor alpha was significantly upregulated. In a rat small bowel transplantation model of allograft rejection treated with HO-1/BMMSCs, we confirmed that the level of miR-200b in the transplanted small bowel tissue was increased significantly, while the level of HMGB3/JNK was downregulated significantly. In conclusion, we identified that exosomes derived from HO-1/BMMSCs play an important role in alleviating the inflammatory injury of IECs. The mechanism is related to miR-200b targeting the abnormally increased expression of the Hmgb3 gene in IECs induced by inflammatory injury. The reduced level of HMGB3 then decreases the inflammatory injury.

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Section: Discussionmentioning

confidence: 99%

MiR-200b in heme oxygenase-1-modified bone marrow mesenchymal stem cell-derived exosomes alleviates inflammatory injury of intestinal epithelial cells by targeting high mobility group box 3

et al. 2020

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“…Mitochondrial Permeability Transition Pore Inhibitors Mitochondrial membrane depolarization, which is induced by the opening of the mitochondrial permeability transition pore (mPTP) in the mitochondrial membrane, can significantly interrupt ETC and then lead to decreased energy production, increased ROS production, and cell death. Cyclosporine-A (CsA) is a well-known immunosuppressant interacting with cyclophilin A and is clinically used in the treatment of graft rejection and autoimmune diseases, including kidney disease [179]. In addition, CsA is also known as an mPTP inhibitor, which can bind to cyclophilin D of the mPTP and inhibit mPTP opening [180].…”

Section: Pharmacological Agentsmentioning

confidence: 99%

From Physiology to Pathology: The Role of Mitochondria in Acute Kidney Injuries and Chronic Kidney Diseases

Zhang¹,

Miao²,

Xu³

et al. 2023

Kidney Dis

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Background: Renal diseases remain an increasing public health issue affecting millions of people. The kidney is a highly energetic organ that is rich in mitochondria. Numerous studies have demonstrated the important role of mitochondria in maintaining normal kidney function and in the pathogenesis of various renal diseases, including acute kidney injuries (AKI) and chronic kidney diseases (CKD). Summary: Under physiological conditions, fine-tuning mitochondrial energy balance, mitochondrial dynamics (fission and fusion processes), mitophagy, and biogenesis maintain mitochondrial fitness. While under AKI and CKD conditions, disruption of mitochondrial energy metabolism leads to increased oxidative stress. In addition, mitochondrial dynamics shift to excessive mitochondrial fission, mitochondrial autophagy is impaired, and mitochondrial biogenesis is also compromised. These mitochondrial injuries regulate renal cellular functions either directly or indirectly. Mitochondria-targeted approaches, containing genetic (microRNAs) and pharmaceutical methods (mitochondria-targeting antioxidants, mitochondrial permeability pore inhibitors, mitochondrial fission inhibitors, and biogenesis activators) are emerging as important therapeutic strategies for AKI and CKD. Key messages: Mitochondria play a critical role in the pathogenesis of AKI and CKD. This review provides an updated overview of mitochondrial homeostasis under physiological conditions and the involvement of mitochondrial dysfunction in renal diseases. Finally, we summarize the current status of mitochondria-targeted strategies in attenuating renal diseases.

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“…This fraction of "free or loosely" bound heme also termed "labile" is biologically active and high levels of labile heme are considered to be cytotoxic and to aggravate inflammation and tissue injury (9,10). In support of this notion are the findings that the deficiency of the heme-degrading enzyme heme oxygenase-1 aggravates renal injury in different models of nephrotoxicity (11,12).…”

Section: Introductionmentioning

confidence: 99%

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

et al. 2019

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Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-α as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression.

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Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs

Cited by 7 publications

References 41 publications

MiR-200b in heme oxygenase-1-modified bone marrow mesenchymal stem cell-derived exosomes alleviates inflammatory injury of intestinal epithelial cells by targeting high mobility group box 3

MiR-200b in heme oxygenase-1-modified bone marrow mesenchymal stem cell-derived exosomes alleviates inflammatory injury of intestinal epithelial cells by targeting high mobility group box 3

From Physiology to Pathology: The Role of Mitochondria in Acute Kidney Injuries and Chronic Kidney Diseases

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

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