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Special Issue "Nephrotoxicity 2019"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 October 2019).

Special Issue Editor

Prof. Dr. Monica Valentovic
Website
Guest Editor
Department of Pharmacology, Physiology and Toxicology, Toxicology Research Cluster Coordinator, Marshall University School of Medicine, 1 Marshall Drive, 435G Byrd Biotech Science Building, Huntington, WV 25755-938, USA
Interests: nephrotoxicity; hepatotoxicity; cancer chemotherapy drugs; acetaminophen; fungicides; solvents; oxidative stress; 4-hydroxynonenal; proximal tubule; protein carbonylation
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Special Issue Information

Dear Colleagues,

Nephrotoxicity can be mediated through many different xenobiotics, including drugs, disinfection byproducts, environmental chemicals, metals, agricultural products, and solvents. The kidney is critical in the filtration and elimination of many substances from the body, but the kidney is metabolically active in the biotransformation and conjugation of foreign substances. The kidney is a target for toxicity by many structurally diverse chemicals, through poorly understood mechanisms. Part of the susceptibility of the kidney can be attributed to cellular accumulation to levels higher than plasma concentrations due to active transporter influx on the basolateral side of proximal tubular epithelial cells. Additionally, very little is known regarding the impact of nephrotoxic substances on the cell signaling pathways involved in cell death and repair. This Special Issue will focus on examining the mechanisms of nephrotoxicity as well as the potential of confounding factors to increase susceptibility to renal toxicity such as aging or the presence of diseases such as diabetes. Second, this Special Issue will examine potential biomarkers of nephrotoxicity. Third, articles in this Special Issue will address the impact of nephrotoxic substances on cell signaling and protein expression that would influence cell function.

Prof. Dr. Monica Valentovic
Guest Editor

Manuscript Submission Information

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Keywords

  • nephrotoxicity
  • metabolomics
  • biomarkers
  • pharmacogenomics
  • proximal tubule
  • pharmaceutical agents
  • natural products

Published Papers (5 papers)

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Research

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Open AccessArticle
Cadmium and Lead Decrease Cell–Cell Aggregation and Increase Migration and Invasion in Renca Mouse Renal Cell Carcinoma Cells
Int. J. Mol. Sci. 2019, 20(24), 6315; https://doi.org/10.3390/ijms20246315 - 14 Dec 2019
Abstract
Metastatic renal cell carcinoma (RCC) remains an important clinical issue; the 5-year survival rate of patients with metastasis is approximately 12%, while it is 93% in those with localized disease. There is evidence that blood cadmium and lead levels are elevated in RCC. [...] Read more.
Metastatic renal cell carcinoma (RCC) remains an important clinical issue; the 5-year survival rate of patients with metastasis is approximately 12%, while it is 93% in those with localized disease. There is evidence that blood cadmium and lead levels are elevated in RCC. The current studies were designed to assess the impact of cadmium and lead on the progression of RCC. The disruption of homotypic cell–cell adhesion is an essential step in epithelial-to-mesenchymal transition and tumor metastasis. Therefore, we examined the impact of cadmium and lead on the cadherin/catenin complex in Renca cells—a mouse RCC cell line. Lead, but not cadmium, induced a concentration-dependent loss of E-cadherin, while cadmium, but not lead, increased p120-catenin expression, specifically isoform 1 expression. Lead also induced a substantial increase in matrix metalloproteinase-9 levels. Both cadmium and lead significantly decreased the number of Renca cell aggregates, consistent with the disruption of the cadherin/catenin complex. Both metals enhanced wound healing in a scratch assay, and increased cell migration and invasion. These data suggest that cadmium and lead promote RCC progression. Full article
(This article belongs to the Special Issue Nephrotoxicity 2019)
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Open AccessArticle
The Effects of Meldonium on the Renal Acute Ischemia/Reperfusion Injury in Rats
Int. J. Mol. Sci. 2019, 20(22), 5747; https://doi.org/10.3390/ijms20225747 - 15 Nov 2019
Abstract
Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium [...] Read more.
Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our results showed that meldonium decreased animal body mass gain, food and water intake, and carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1, causing manganese superoxide dismutase expression and activity to increase, as well as lipid peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex changes in renal lipidomics. Taken together, our results have confirmed that meldonium pre-treatment protects against I/R-induced oxidative stress and apoptosis/necrosis. Full article
(This article belongs to the Special Issue Nephrotoxicity 2019)
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Open AccessArticle
Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
Int. J. Mol. Sci. 2019, 20(17), 4074; https://doi.org/10.3390/ijms20174074 - 21 Aug 2019
Cited by 1
Abstract
Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital associated kidney damage. Potential mechanisms of CI-AKI may involve diminished renal hemodynamics, inflammatory responses, and direct cytotoxicity. The hypothesis for this study is that diatrizoic acid (DA) induces direct cytotoxicity [...] Read more.
Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital associated kidney damage. Potential mechanisms of CI-AKI may involve diminished renal hemodynamics, inflammatory responses, and direct cytotoxicity. The hypothesis for this study is that diatrizoic acid (DA) induces direct cytotoxicity to human proximal tubule (HK-2) cells via calcium dysregulation, mitochondrial dysfunction, and oxidative stress. HK-2 cells were exposed to 0–30 mg I/mL DA or vehicle for 2–24 h. Conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion indicated a decrease in mitochondrial and cell viability within 2 and 24 h, respectively. Mitochondrial dysfunction was apparent within 8 h post exposure to 15 mg I/mL DA as shown by Seahorse XF cell mito and Glycolysis Stress tests. Mitophagy was increased at 8 h by 15 mg I/mL DA as confirmed by elevated LC3BII/I expression ratio. HK-2 cells pretreated with calcium level modulators BAPTA-AM, EGTA, or 2-aminophenyl borinate abrogated DA-induced mitochondrial damage. DA increased oxidative stress biomarkers of protein carbonylation and 4-hydroxynonenol (4HNE) adduct formation. Caspase 3 and 12 activation was induced by DA compared to vehicle at 24 h. These studies indicate that clinically relevant concentrations of DA impair HK-2 cells by dysregulating calcium, inducing mitochondrial turnover and oxidative stress, and activating apoptosis. Full article
(This article belongs to the Special Issue Nephrotoxicity 2019)
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Review

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Open AccessReview
The Role of IgA in the Pathogenesis of IgA Nephropathy
Int. J. Mol. Sci. 2019, 20(24), 6199; https://doi.org/10.3390/ijms20246199 - 09 Dec 2019
Abstract
Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable [...] Read more.
Immunoglobulin A (IgA) is the most abundant antibody isotype produced in humans, predominantly present in the mucosal areas where its main functions are the neutralization of toxins, prevention of microbial invasion across the mucosal epithelial barrier, and simultaneous maintenance of a physiologically indispensable symbiotic relationship with commensal bacteria. The process of IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy, which is the most common form of glomerulonephritis worldwide. This review summarizes the latest findings in the complex characteristics of the molecular structure and biological functions of IgA antibodies, offering an in-depth overview of recent advances in the understanding of biochemical, immunologic, and genetic factors important in the pathogenesis of IgA nephropathy. Full article
(This article belongs to the Special Issue Nephrotoxicity 2019)
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Open AccessReview
The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity
Int. J. Mol. Sci. 2019, 20(20), 5238; https://doi.org/10.3390/ijms20205238 - 22 Oct 2019
Cited by 2
Abstract
Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying [...] Read more.
Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI. Full article
(This article belongs to the Special Issue Nephrotoxicity 2019)
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