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Renal Toxicology—Epidemiology and Mechanisms
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Renal Toxicology—Epidemiology and Mechanisms

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 (15 July 2014) | Viewed by 43633

Special Issue Editor

Prof. Dr. Gary O. Rankin

E-Mail Website
Guest Editor
Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, One John Marshall Drive, Huntington, WV 25755, USA
Interests: nephrotoxicity mechanisms; renal bioactivation of toxicants; structure-toxicity relationships
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The kidney is a target for many types of chemicals including drugs, agricultural agents, industrial chemicals and environmental pollutants. While an important function of the kidney is to eliminate xenobiotics and their metabolites, the kidney also has the ability to accumulate and concentrate chemicals to toxic levels via renal transport systems and urinary concentrating mechanisms. The kidneys can also bioactivate chemicals via a variety of enzyme systems to toxic metabolites that cause acute and/or chronic renal injury. Recent studies on genetic polymorphisms are also beginning to provide some insight into nephrotoxic mechanisms. However, for many nephrotoxicants, the mechanisms and contributing renal factors that lead to renal injury are poorly understood. Epidemiological studies have also revealed increased renal injury due to exposure to therapeutic agents as well as chemicals in the environment, and provided insight into the nephrotoxic potential of various chemicals and susceptible human populations. Nonetheless, additional epidemiological information is needed for many renal toxicants. Articles in this special issue will address research directed toward defining mechanisms and contributing factors leading to renal toxicity. In addition, this special issue will address epidemiological information related to nephrotoxicity related to chemical exposure.

Prof. Dr. Gary O. Rankin
Guest Editor

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Keywords

  • nephrotoxic mechanisms
  • bioactivation of nephrotoxicants
  • toxicogenomics
  • nephrotoxic epidemiology

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Published Papers (5 papers)

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Research

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8401 KiB  
Article
Multigenerational Study of Chemically Induced Cytotoxicity and Proliferation in Cultures of Human Proximal Tubular Cells
by Lawrence H. Lash, David A. Putt and Bavneet Benipal
Int. J. Mol. Sci. 2014, 15(11), 21348-21365; https://doi.org/10.3390/ijms151121348 - 18 Nov 2014
Cited by 4 | Viewed by 5149
Abstract
Primary cultures of human proximal tubular (hPT) cells are a useful experimental model to study transport, metabolism, cytotoxicity, and effects on gene expression of a diverse array of drugs and environmental chemicals because they are derived directly from the in vivo human kidney. [...] Read more.
Primary cultures of human proximal tubular (hPT) cells are a useful experimental model to study transport, metabolism, cytotoxicity, and effects on gene expression of a diverse array of drugs and environmental chemicals because they are derived directly from the in vivo human kidney. To extend the model to investigate longer-term processes, primary cultures (P0) were passaged for up to four generations (P1–P4). hPT cells retained epithelial morphology and stained positively for cytokeratins through P4, although cell growth and proliferation successively slowed with each passage. Necrotic cell death due to the model oxidants tert-butyl hydroperoxide (tBH) and methyl vinyl ketone (MVK) increased with increasing passage number, whereas that due to the selective nephrotoxicant S-(1,2-dichlorovinyl)-l-cysteine (DCVC) was modest and did not change with passage number. Mitochondrial activity was lower in P2–P4 cells than in either P0 or P1 cells. P1 and P2 cells were most sensitive to DCVC-induced apoptosis. DCVC also increased cell proliferation most prominently in P1 and P2 cells. Modest differences with respect to passage number and response to DCVC exposure were observed in expression of three key proteins (Hsp27, GADD153, p53) involved in stress response. Hence, although there are some modest differences in function with passage, these results support the use of multiple generations of hPT cells as an experimental model. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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666 KiB  
Article
3,4,5-Trichloroaniline Nephrotoxicity in Vitro: Potential Role of Free Radicals and Renal Biotransformation
by Christopher Racine, Dakota Ward, Dianne K. Anestis, Travis Ferguson, Deborah Preston and Gary O. Rankin
Int. J. Mol. Sci. 2014, 15(11), 20900-20912; https://doi.org/10.3390/ijms151120900 - 13 Nov 2014
Cited by 6 | Viewed by 6828
Abstract
Chloroanilines are widely used in the manufacture of drugs, pesticides and industrial intermediates. Among the trichloroanilines, 3,4,5-trichloroaniline (TCA) is the most potent nephrotoxicant in vivo. The purpose of this study was to examine the nephrotoxic potential of TCA in vitro and to [...] Read more.
Chloroanilines are widely used in the manufacture of drugs, pesticides and industrial intermediates. Among the trichloroanilines, 3,4,5-trichloroaniline (TCA) is the most potent nephrotoxicant in vivo. The purpose of this study was to examine the nephrotoxic potential of TCA in vitro and to determine if renal biotransformation and/or free radicals contributed to TCA cytotoxicity using isolated renal cortical cells (IRCC) from male Fischer 344 rats as the animal model. IRCC (~4 million cells/mL; 3 mL) were incubated with TCA (0, 0.1, 0.25, 0.5 or 1.0 mM) for 60–120 min. In some experiments, IRCC were pretreated with an antioxidant or a cytochrome P450 (CYP), flavin monooxygenase (FMO), cyclooxygenase or peroxidase inhibitor prior to incubation with dimethyl sulfoxide (control) or TCA (0.5 mM) for 120 min. At 60 min, TCA did not induce cytotoxicity, but induced cytotoxicity as early as 90 min with 0.5 mM or higher TCA and at 120 min with 0.1 mM or higher TCA, as evidenced by increased lactate dehydrogenase (LDH) release. Pretreatment with the CYP inhibitor piperonyl butoxide, the cyclooxygenase inhibitor indomethacin or the peroxidase inhibitor mercaptosuccinate attenuated TCA cytotoxicity, while pretreatment with FMO inhibitors or the CYP inhibitor metyrapone had no effect on TCA nephrotoxicity. Pretreatment with an antioxidant (α-tocopherol, glutathione, ascorbate or N-acetyl-l-cysteine) also reduced or completely blocked TCA cytotoxicity. These results indicate that TCA is directly nephrotoxic to IRCC in a time and concentration dependent manner. Bioactivation of TCA to toxic metabolites by CYP, cyclooxygenase and/or peroxidase contributes to the mechanism of TCA nephrotoxicity. Lastly, free radicals play a role in TCA cytotoxicity, although the exact nature of the origin of these radicals remains to be determined. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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2146 KiB  
Article
Transition from Cyclosporine-Induced Renal Dysfunction to Nephrotoxicity in an in Vivo Rat Model
by José Sereno, Paulo Rodrigues-Santos, Helena Vala, Petronila Rocha-Pereira, Rui Alves, João Fernandes, Alice Santos-Silva, Eugénia Carvalho, Frederico Teixeira and Flávio Reis
Int. J. Mol. Sci. 2014, 15(5), 8979-8997; https://doi.org/10.3390/ijms15058979 - 20 May 2014
Cited by 25 | Viewed by 8638
Abstract
Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical [...] Read more.
Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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Review

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871 KiB  
Review
Cadmium Transporters in the Kidney and Cadmium-Induced Nephrotoxicity
by Hong Yang and Yan Shu
Int. J. Mol. Sci. 2015, 16(1), 1484-1494; https://doi.org/10.3390/ijms16011484 - 9 Jan 2015
Cited by 175 | Viewed by 12156
Abstract
Among the organs in which the environmental pollutant cadmium causes toxicity, the kidney has gained the most attention in recent years. Numerous studies have sought to unravel the exact pathways by which cadmium enters the renal epithelial cells and the mechanisms by which [...] Read more.
Among the organs in which the environmental pollutant cadmium causes toxicity, the kidney has gained the most attention in recent years. Numerous studies have sought to unravel the exact pathways by which cadmium enters the renal epithelial cells and the mechanisms by which it causes toxicity in the kidney. The purpose of this review is to present the progress made on the mechanisms of cadmium transport in the kidney and the role of transporter proteins in cadmium-induced nephrotoxicity. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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969 KiB  
Review
The Aging Kidney: Increased Susceptibility to Nephrotoxicity
by Xinhui Wang, Joseph V. Bonventre and Alan R. Parrish
Int. J. Mol. Sci. 2014, 15(9), 15358-15376; https://doi.org/10.3390/ijms150915358 - 1 Sep 2014
Cited by 109 | Viewed by 10232
Abstract
Three decades have passed since a series of studies indicated that the aging kidney was characterized by increased susceptibility to nephrotoxic injury. Data from these experimental models is strengthened by clinical data demonstrating that the aging population has an increased incidence and severity [...] Read more.
Three decades have passed since a series of studies indicated that the aging kidney was characterized by increased susceptibility to nephrotoxic injury. Data from these experimental models is strengthened by clinical data demonstrating that the aging population has an increased incidence and severity of acute kidney injury (AKI). Since then a number of studies have focused on age-dependent alterations in pathways that predispose the kidney to acute insult. This review will focus on the mechanisms that are altered by aging in the kidney that may increase susceptibility to injury, including hemodynamics, oxidative stress, apoptosis, autophagy, inflammation and decreased repair. Full article
(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)
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