Myeloid-Derived Suppressor Cells Induce Podocyte Injury Through Increasing Reactive Oxygen Species in Lupus Nephritis

Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.

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Reactive Oxygen Species-initiated Autophagy Opposes Aldosterone-induced Podocyte Injury

Hong Kong Journal of Nephrology ◽

10.1016/j.hkjn.2015.09.131 ◽

2015 ◽

Vol 17 (2) ◽

pp. S87 ◽

Cited By ~ 1

Author(s):

M. Bai ◽

R.C. Che ◽

A.H. Zhang

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species ◽

Podocyte Injury

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Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011297117 ◽

2020 ◽

Vol 117 (52) ◽

pp. 32962-32969

Author(s):

Zhaoting Li ◽

Lianghan Zhu ◽

Honghao Sun ◽

Yuexin Shen ◽

Dandan Hu ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Immune Response ◽

T Cells ◽

Immune Activation ◽

Suppressor Cells ◽

Immunogenic Cell Death ◽

Myeloid Derived Suppressor Cells ◽

Oxygen Species ◽

Clinical Investigations ◽

Immunosuppressive Cells

Clinical investigations have shown that a nonimmunogenic “cold” tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor “hot.” Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.

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TGF-β1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00182.2013 ◽

2013 ◽

Vol 305 (10) ◽

pp. F1477-F1490 ◽

Cited By ~ 46

Author(s):

Yoshifusa Abe ◽

Toru Sakairi ◽

Craig Beeson ◽

Jeffrey B. Kopp

Keyword(s):

Reactive Oxygen Species ◽

Oxygen Consumption ◽

Transforming Growth Factor ◽

Reactive Oxygen ◽

Mtor Pathway ◽

Oxygen Species ◽

Podocyte Injury ◽

Mitochondrial Dna Copy Number ◽

Atp Generation ◽

Tgf Β1

Transforming growth factor (TGF)-β has been associated with podocyte injury; we have examined its effect on podocyte bioenergetics. We studied transformed mouse podocytes, exposed to TGF-β1, using a label-free assay system, Seahorse XF24, which measures oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Both basal OCR and ATP generation-coupled OCR were significantly higher in podocytes exposed to 0.3–10 ng/ml of TGF-β1 for 24, 48, and 72 h. TGF-β1 (3 ng/ml) increased oxidative capacity 75%, and 96% relative to control after 48 and 72 h, respectively. ATP content was increased 19% and 30% relative to control after a 48- and 72-h exposure, respectively. Under conditions of maximal mitochondrial function, TGF-β1 increased palmitate-driven OCR by 49%. Thus, TGF-β1 increases mitochondrial oxygen consumption and ATP generation in the presence of diverse energy substrates. TGF-β1 did not increase cell number or mitochondrial DNA copy number but did increase mitochondrial membrane potential (MMP), which could explain the OCR increase. Reactive oxygen species (ROS) increased by 32% after TGF-β1 exposure for 48 h. TGF-β activated the mammalian target of rapamycin (mTOR) pathway, and rapamycin reduced the TGF-β1-stimulated increases in OCR, ECAR, ATP generation, cellular metabolic activity, and protein generation. Our data suggest that TGF-β1, acting, in part, via mTOR, increases mitochondrial MMP and OCR, resulting in increased ROS generation and that this may contribute to podocyte injury.

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PENGARUH PEMBERIAN N-ASETILSISTEIN TERHADAP EKSPRESI CASPASE-1 GLOMERULUS DAN DERAJAT KERUSAKAN GINJAL PADA MENCIT NEFRITIS LUPUS INDUKSI PRISTAN

Biomedika ◽

10.23917/biomedika.v10i2.7015 ◽

2018 ◽

Vol 10 (2) ◽

Author(s):

Anindita Rachmawati ◽

Bambang Purwanto ◽

Diding Heri Prasetyo

Keyword(s):

Reactive Oxygen Species ◽

Lupus Nephritis ◽

Renal Injury ◽

Active Form ◽

Reactive Oxygen ◽

Kidney Injury ◽

Basal Membrane ◽

Control Group ◽

Oxygen Species ◽

Caspase 1

ABSTRAKLupus nefritis (LN) terkait dengan penebalan membran basal glomerulus. Pengendapan kompleks imun memicu kaskade respon inflamasi disertai aktivasi reactive oxygen species (ROS), akhirnya terjadi aktivasi caspase-1, dan caspase-1, mengaktifkan IL-1B dan IL-18 yang berlanjut terjadinya apoptosis dan nekrosis dan akhirnya terjadi kerusakan ginjal. Peningkatan ekspresi caspase-1 dapat dicegah oleh N-Asetil Sistein (NAS), yang merupakan suatu senyawa dengan efek antioksidan dan antiinflamasi. Penelitian ini bertujuan untuk mengetahui pengaruh NAS terhadap ekspresi caspase-1 dan terjadinya apoptosis dan nekrosis ginjal pada mencit model lupus nefritis. Penelitian ini merupakan penelitian eksperimental laboratoris, dengan sampel 24 ekor mencit Balb/C betina yang dibagi menjadi kelompok kontrol, LN, dan LN+NAS. Untuk membuat model LN, hewan coba diberikan injeksi 0,5 ml pristan intraperitoneal dosis tunggal. NAS diberikan secara peroral dengan dosis 4,7 mg/hari) selama delapan minggu. Mencit kontrol tidak diinokulasi selama penelitian. Ekspresi caspase-1 dihitung dari 100 sel makrofag yang immunoreaktif dengan teknik imunohistokimia dan kejadian apoptosis dan nekrosis dihitung dengan dengan teknik histopatologi. Hasil penelitian menunjukkan bahwa, pemberian NAS menurunkan ekspresi caspase-1 (22,8 ± 6,4 vs 31,4 ± 7,5 per 100 sel makrofag imunoreaktif; p = 0,000) dan menurunkan kerusakan ginjal (6,75 ± 2,92 vs 9,88 ± 3,56; p =0,010) dibandingkan kelompok LN. NAS secara bermakna menurunkan ekspresi caspase-1 dan derajat kerusakan ginjal pada mencit model LN. Kata Kunci: Caspase-1, Derajat Kerusakan Ginjal, Lupus Nefritis, Pristan ABSTRACTLupus nephritis (LN) associated with thickening of the basal membrane of the glomerulus. The deposition of immune complexes trigger a cascade of inflammatory response accompanied the activation of reactive oxygen species (ROS), finally happened activation caspase-1, and enable the IL-1B and IL-18 to be the active form, and to be continued into occurrence of apoptosis and necrosis and eventually the kidney injury. Increased of caspase-1 expression can be prevented by N-Acetyl Cysteine (NAS), which is a compound with antioxidant and anti-inflammatory effects.This study aimed to analyze the effects of NAS on the expression of Caspase-1 and degree of renal injury in mice models of lupus nephritis. This study is an experimental research laboratory, with a sample of 24 females Balb/C mice were divided into a control group, LN and LN+NAS. To create a model LN, experimental animals given intraperitoneal injection of 0.5 ml Pristan single dose. NAS administered orally at a dose of 4.7 mg/day for eight weeks. Control mice not inoculated during the study. Expression of Caspase-1 was calculated from 100 macrophage cells immunoreactive with immunohistochemical and degree of renal injury with histopathological techniques. One way analysis of variance (Anova) for caspase-1 expression and degree of renal injury, and p<0.05 were used to determine the significant differences. The provision of NAS decreased the expression of caspase-1 (22,8 ± 6,4 vs 31,4 ± 7,5 per 100 macrophage immunoreactive cells; p = 0.042) and degree of renal injury (6,75 ± 2,92 vs 9,88 ± 3,56; p =0,010) compared to LN group respectively. NAS significantly decrease the expression of caspase-1 and degree of renal injury in mice models LN.Keywords: Caspase-1, Degree Of Renal Injury, Lupus Nephritis, Pristane

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