Pharmacological Interventions for the Prevention and Treatment of Kidney Injury Induced by Radiotherapy: Molecular Mechanisms and Clinical Perspectives

: More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radio-protective properties on amelioration of inﬂammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.

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Oral Sequelae of Head and Neck Radiotherapy

Critical Reviews in Oral Biology & Medicine ◽

10.1177/154411130301400305 ◽

2003 ◽

Vol 14 (3) ◽

pp. 199-212 ◽

Cited By ~ 479

Author(s):

A. Vissink ◽

J. Jansma ◽

F.K.L. Spijkervet ◽

F.R. Burlage ◽

R.P. Coppes

Keyword(s):

Head And Neck ◽

Neck Region ◽

Normal Tissues ◽

Radiation Caries ◽

Temporomandibular Joints ◽

Clinical Consequences ◽

Radiation Induced ◽

Heavy Burden ◽

Effects Of Radiation ◽

Induced Changes

In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus. Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible. Furthermore, the risk of developing radiation caries and osteoradionecrosis is a life-long threat. All these consequences form a heavy burden for the patients and have a tremendous impact on their quality of life during and after radiotherapy. In this review, the radiation-induced changes in healthy oral tissues and the resulting clinical consequences are discussed.

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Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

Antioxidants ◽

10.3390/antiox10111666 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1666

Author(s):

Zijing Liu ◽

Lihua Dong ◽

Zhuangzhuang Zheng ◽

Shiyu Liu ◽

Shouliang Gong ◽

...

Keyword(s):

Oxidative Stress ◽

Head And Neck ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

Serious Adverse Event ◽

Oral Infections ◽

Normal Tissues ◽

Radiation Induced ◽

Swallowing Muscles

Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient’s quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.

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Podocyte and tubular involvement in AngioJet-induced kidney injury

Clinical Kidney Journal ◽

10.1093/ckj/sfz104 ◽

2019 ◽

Author(s):

Raquel Esteras ◽

Pablo Cannata-Ortiz ◽

Marta del Palacio-Tamarit ◽

Melania Guerrero-Hue ◽

Cristina García-Caballero ◽

...

Keyword(s):

Oxidative Stress ◽

Adaptive Response ◽

Mechanical Thrombectomy ◽

Cell Injury ◽

Kidney Injury ◽

Tubular Injury ◽

Histological Evidence ◽

Cellular Targets ◽

Percutaneous Mechanical Thrombectomy ◽

Renal Biopsies

Abstract The AngioJet technique combines localized thrombolysis and percutaneous mechanical thrombectomy (PMT). However, PMT may cause acute kidney injury (AKI), which has been ascribed to severe mechanical haemolysis, although no renal biopsies have been reported. We now report the first renal biopsy in a patient with AKI following PMT. There is histological evidence of haemoglobin (Hb)-induced tubular injury and podocyte stress characterized by intracellular Hb and staining for ferritin and hemo-oxygenase-1, suggestive of an adaptive response to oxidative stress. This confirms that Hb is involved in kidney cell injury and supports the existence of several different kidney cellular targets.

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Radiation-induced kidney injury: a role for chronic oxidative stress?

Micron ◽

10.1016/s0968-4328(01)00006-3 ◽

2002 ◽

Vol 33 (2) ◽

pp. 133-141 ◽

Cited By ~ 52

Author(s):

Mike E.C Robbins ◽

Weiling Zhao ◽

Charles S Davis ◽

Shinya Toyokuni ◽

Stephen M Bonsib

Keyword(s):

Oxidative Stress ◽

Kidney Injury ◽

Chronic Oxidative Stress ◽

Radiation Induced

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Isoquercitrin Ameliorates Cisplatin-Induced Nephrotoxicity Via the Inhibition of Apoptosis, Inﬂammation, and Oxidative Stress

Frontiers in Pharmacology ◽

10.3389/fphar.2020.599416 ◽

2020 ◽

Vol 11 ◽

Author(s):

Hao Wang ◽

Weiwei Xia ◽

Guangfeng Long ◽

Zhiyin Pei ◽

Yuanyuan Li ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Function ◽

Cell Injury ◽

Kidney Diseases ◽

Kidney Injury ◽

Epithelial Cell Line ◽

Therapeutic Uses ◽

And Oxidative Stress

Cisplatin is extensively used and is highly effective in clinical oncology; nevertheless, nephrotoxicity has severely limited its widespread utility. Isoquercitrin (IQC), a natural flavonoid widely found in herbage, is well known and recognized for its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the potential effects and mechanism of IQC in cisplatin-induced acute kidney diseases remain unknown. In this study, we postulated the potential effects and mechanism of IQC upon cisplatin exposure in vivo and in vitro. For the in vivo study, C57BL/6J mice were pretreated with IQC or saline (50 mg/kg/day) by gavage for 3 days before cisplatin single injection (25 mg/kg). Renal function, apoptosis, inflammation, oxidative stress and p-ERK were measured to evaluate kidney injury. In vitro, mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cell line (HK2) were pretreated with or without IQC (80 μM for mPTCs and 120 μM for HK2) for 2 h and then co-administrated with cisplatin for another 24 h. Apoptosis, inflammation, ROS and p-ERK of cells were also measured. In vivo, IQC administration strikingly reduced cisplatin-induced nephrotoxicity as evidenced by the improvement in renal function (serum creatinine and blood urea nitrogen), kidney histology (PAS staining), apoptotic molecules (cleaved caspase-3, caspase-8, Bax and Bcl-2), inﬂammatory cytokines (IL-1β, IL-6, TNF-α, and COX-2), oxidative stress (MDA and total glutathione) and p-ERK. In line with in vivo findings, IQC markedly protected against cisplatin-induced cell injury in mPTCs and HK2 cells. Collectively, these findings demonstrated that IQC administration could significantly protect against cisplatin nephrotoxicity possibly through ameliorating apoptosis, inflammation and oxidative stress accompanied by cross talk with p-ERK. Furthermore, IQC may have potential therapeutic uses in the treatment of cisplatin-induced acute kidney injury.

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Naringin ameliorates radiation-induced hepatic damage through modulation of Nrf2 and NF-κB pathways

RSC Advances ◽

10.1039/c6ra01102k ◽

2016 ◽

Vol 6 (27) ◽

pp. 23058-23073 ◽

Cited By ~ 11

Author(s):

Krishnendu Manna ◽

Amitava Khan ◽

Sushobhan Biswas ◽

Ujjal Das ◽

Aaveri Sengupta ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Signaling ◽

Hepatic Damage ◽

Toxic Effects ◽

Signaling System ◽

System P ◽

Murine Liver ◽

Radiation Induced ◽

Effects Of Radiation

Naringin ameliorates the toxic effects of radiation in murine liver and decreases the oxidative stress through the modulation of redox-regulated cellular signaling system.

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Microarray analysis to identify molecular mechanisms of radiation-induced microvascular damage in normal tissues

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2003.09.031 ◽

2004 ◽

Vol 58 (2) ◽

pp. 420-426 ◽

Cited By ~ 34

Author(s):

Jacqueline J.C.M Kruse ◽

Johannes A.M te Poele ◽

Nicola S Russell ◽

Liesbeth J Boersma ◽

Fiona A Stewart

Keyword(s):

Microarray Analysis ◽

Molecular Mechanisms ◽

Microvascular Damage ◽

Normal Tissues ◽

Radiation Induced

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5 Oral Identification of molecular mechanisms of radiation-induced vascular damage in normal tissues using microarray analyses

Radiotherapy and Oncology ◽

10.1016/s0167-8140(03)80541-8 ◽

2003 ◽

Vol 67 ◽

pp. S2

Keyword(s):

Molecular Mechanisms ◽

Vascular Damage ◽

Normal Tissues ◽

Radiation Induced ◽

Microarray Analyses

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PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis

Cell Death and Disease ◽

10.1038/s41419-021-04480-3 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Bo Young Nam ◽

Jong Hyun Jhee ◽

Jimin Park ◽

Seonghun Kim ◽

Gyuri Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Cell Injury ◽

Mitochondrial Dynamics ◽

Kidney Injury ◽

Negative Regulator ◽

Mitochondrial Dynamic ◽

Kidney Fibrosis ◽

Tgf Β1

AbstractThe NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-β1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-β1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-β1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.

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