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Nephrotoxicity 2022

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 (31 December 2022) | Viewed by 12848

Special Issue Editor


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Guest Editor
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, 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. This Special Issue will also examine potential biomarkers of nephrotoxicity. Additionally, articles in this Special Issue will address the impact of nephrotoxic substances on cell signaling and protein expression that influence cell function.

Prof. Dr. Monica Valentovic
Guest Editor

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Keywords

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

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Published Papers (5 papers)

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Research

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29 pages, 10540 KiB  
Article
Insights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines
by B. Alex Merrick, Negin P. Martin, Ashley M. Brooks, Julie F. Foley, Paul E. Dunlap, Sreenivasa Ramaiahgari, Rick D. Fannin and Kevin E. Gerrish
Int. J. Mol. Sci. 2023, 24(18), 14228; https://doi.org/10.3390/ijms241814228 - 18 Sep 2023
Cited by 1 | Viewed by 2211
Abstract
Renal proximal tubule epithelial cells (RPTECs) are a primary site for kidney injury. We created two RPTEC lines from CD-1 mice immortalized with hTERT (human telomerase reverse transcriptase) or SV40 LgT antigen (Simian Virus 40 Large T antigen). Our hypothesis was that low-level, [...] Read more.
Renal proximal tubule epithelial cells (RPTECs) are a primary site for kidney injury. We created two RPTEC lines from CD-1 mice immortalized with hTERT (human telomerase reverse transcriptase) or SV40 LgT antigen (Simian Virus 40 Large T antigen). Our hypothesis was that low-level, repeated exposure to subcytotoxic levels of 0.25–2.5 μM cisplatin (CisPt) or 12.5–100 μM aflatoxin B1 (AFB1) would activate distinctive genes and pathways in these two differently immortalized cell lines. RNA-seq showed only LgT cells responded to AFB1 with 1139 differentially expressed genes (DEGs) at 72 h. The data suggested that AFB1 had direct nephrotoxic properties on the LgT cells. However, both the cell lines responded to 2.5 μM CisPt from 3 to 96 h expressing 2000–5000 total DEGs. For CisPt, the findings indicated a coordinated transcriptional program of injury signals and repair from the expression of immune receptors with cytokine and chemokine secretion for leukocyte recruitment; robust expression of synaptic and substrate adhesion molecules (SAMs) facilitating the expression of neural and hormonal receptors, ion channels/transporters, and trophic factors; and the expression of nephrogenesis transcription factors. Pathway analysis supported the concept of a renal repair transcriptome. In summary, these cell lines provide in vitro models for the improved understanding of repeated renal injury and repair mechanisms. High-throughput screening against toxicant libraries should provide a wider perspective of their capabilities in nephrotoxicity. Full article
(This article belongs to the Special Issue Nephrotoxicity 2022)
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19 pages, 5638 KiB  
Article
Arsenite Exposure to Human RPCs (HRTPT) Produces a Reversible Epithelial Mesenchymal Transition (EMT): In-Vitro and In-Silico Study
by Sonalika Singhal, Scott H. Garrett, Seema Somji, Kalli Schaefer, Benu Bansal, Jappreet Singh Gill, Sandeep K. Singhal and Donald A. Sens
Int. J. Mol. Sci. 2023, 24(6), 5092; https://doi.org/10.3390/ijms24065092 - 7 Mar 2023
Viewed by 1456
Abstract
The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) [...] Read more.
The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media. Full article
(This article belongs to the Special Issue Nephrotoxicity 2022)
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21 pages, 4876 KiB  
Article
Magnesium Isoglycyrrhizinate Reduces the Target-Binding Amount of Cisplatin to Mitochondrial DNA and Renal Injury through SIRT3
by Xinyu Wang, Hutailong Zhu, Jiayin Hu, Haobin Li, Suhan Guo, Bin Chen, Changxiao Liu, Guangji Wang and Fang Zhou
Int. J. Mol. Sci. 2022, 23(21), 13093; https://doi.org/10.3390/ijms232113093 - 28 Oct 2022
Cited by 5 | Viewed by 1993
Abstract
Nephrotoxicity is the dose-limiting factor of cisplatin treatment. Magnesium isoglycyrrhizinate (MgIG) has been reported to ameliorate renal ischemia–reperfusion injury. This study aimed to investigate the protective effect and possible mechanisms of MgIG against cisplatin-induced nephrotoxicity from the perspective of cellular pharmacokinetics. We found [...] Read more.
Nephrotoxicity is the dose-limiting factor of cisplatin treatment. Magnesium isoglycyrrhizinate (MgIG) has been reported to ameliorate renal ischemia–reperfusion injury. This study aimed to investigate the protective effect and possible mechanisms of MgIG against cisplatin-induced nephrotoxicity from the perspective of cellular pharmacokinetics. We found that cisplatin predominantly accumulated in mitochondria of renal tubular epithelial cells, and the amount of binding with mitochondrial DNA (mtDNA) was more than twice that with nuclear DNA (nDNA). MgIG significantly lowered the accumulation of cisplatin in mitochondria and, in particular, the degree of target-binding to mtDNA. MgIG notably ameliorated cisplatin-induced changes in mitochondrial membrane potential, morphology, function, and cell viability, while the magnesium donor drugs failed to work. In a mouse model, MgIG significantly alleviated cisplatin-caused renal dysfunction, pathological changes of renal tubules, mitochondrial ultrastructure variations, and disturbed energy metabolism. Both in vitro and in vivo data showed that MgIG recovered the reduction of NAD+-related substances and NAD+-dependent deacetylase sirtuin-3 (SIRT3) level caused by cisplatin. Furthermore, SIRT3 knockdown weakened the protective effect of MgIG on mitochondria, while SIRT3 agonist protected HK-2 cells from cisplatin and specifically reduced platinum-binding activity with mtDNA. In conclusion, MgIG reduces the target-binding amount of platinum to mtDNA and exerts a protective effect on cisplatin-induced renal injury through SIRT3, which may provide a new strategy for the treatment of cisplatin-induced nephrotoxicity. Full article
(This article belongs to the Special Issue Nephrotoxicity 2022)
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16 pages, 18718 KiB  
Article
The Urinary Level of Injury Biomarkers Is Not Univocally Reflective of the Extent of Toxic Renal Tubular Injury in Rats
by Sandra M. Sancho-Martínez, María Herrero, Miguel Fontecha-Barriuso, Joana Mercado-Hernández and Francisco J. López-Hernández
Int. J. Mol. Sci. 2022, 23(7), 3494; https://doi.org/10.3390/ijms23073494 - 23 Mar 2022
Cited by 4 | Viewed by 2004
Abstract
Nephrotoxicity is a major cause of intrinsic acute kidney injury (AKI). Because renal tissue damage may occur independently of a reduction in glomerular filtration rate and of elevations in plasma creatinine concentration, so-called injury biomarkers have been proposed to form part of diagnostic [...] Read more.
Nephrotoxicity is a major cause of intrinsic acute kidney injury (AKI). Because renal tissue damage may occur independently of a reduction in glomerular filtration rate and of elevations in plasma creatinine concentration, so-called injury biomarkers have been proposed to form part of diagnostic criteria as reflective of tubular damage independently of renal function status. We studied whether the urinary level of NGAL, KIM-1, GM2AP, t-gelsolin, and REGIIIb informed on the extent of tubular damage in rat models of nephrotoxicity, regardless of the etiology, moment of observation, and underlying pathophysiology. At a time of overt AKI, urinary biomarkers were measured by Western blot or ELISA, and tubular necrosis was scored from histological specimens stained with hematoxylin and eosin. Correlation and regression studies revealed that only weak relations existed between biomarkers and tubular damage. Due to high interindividual variability in the extent of damage for any given biomarker level, urinary injury biomarkers did not necessarily reflect the extent of the underlying tissue injury in individual rats. We contended, in this work, that further pathophysiological contextualization is necessary to understand the diagnostic significance of injury biomarkers before they can be used for renal tubular damage severity stratification in the context of nephrotoxic and, in general, intrinsic AKI. Full article
(This article belongs to the Special Issue Nephrotoxicity 2022)
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Review

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28 pages, 2622 KiB  
Review
Molecular Mechanisms of Acute Organophosphate Nephrotoxicity
by Vladislav E. Sobolev, Margarita O. Sokolova, Richard O. Jenkins and Nikolay V. Goncharov
Int. J. Mol. Sci. 2022, 23(16), 8855; https://doi.org/10.3390/ijms23168855 - 9 Aug 2022
Cited by 13 | Viewed by 4184
Abstract
Organophosphates (OPs) are toxic chemicals produced by an esterification process and some other routes. They are the main components of herbicides, pesticides, and insecticides and are also widely used in the production of plastics and solvents. Acute or chronic exposure to OPs can [...] Read more.
Organophosphates (OPs) are toxic chemicals produced by an esterification process and some other routes. They are the main components of herbicides, pesticides, and insecticides and are also widely used in the production of plastics and solvents. Acute or chronic exposure to OPs can manifest in various levels of toxicity to humans, animals, plants, and insects. OPs containing insecticides were widely used in many countries during the 20th century, and some of them continue to be used today. In particular, 36 OPs have been registered in the USA, and all of them have the potential to cause acute and sub-acute toxicity. Renal damage and impairment of kidney function after exposure to OPs, accompanied by the development of clinical manifestations of poisoning back in the early 1990s of the last century, was considered a rare manifestation of their toxicity. However, since the beginning of the 21st century, nephrotoxicity of OPs as a manifestation of delayed toxicity is the subject of greater attention of researchers. In this article, we present a modern view on the molecular pathophysiological mechanisms of acute nephrotoxicity of organophosphate compounds. Full article
(This article belongs to the Special Issue Nephrotoxicity 2022)
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