UNASSIGNED: This study explores the possible therapeutic role of rats and mice bone marrow-derived mesenchymal stem cells (BM-MSCs) on renal damage and toxicity brought on by carbon tetrachloride (CCl4) in Wistar rats.
UNASSIGNED: Following an intraperitoneal injection of CCl4 (0.5 mL/kg b.w. twice weekly) for eight weeks, male Wistar rats were intravenously treated with rats and mice BM-MSCs (1 × 106 cells in 0.2 mL Dulbecco\'s Modified Eagle Medium (DMEM)/rat/week) a week for four weeks. Kidney functions were evaluated and kidney samples were examined using hematoxylin and eosin (H&E), Masson\'s trichrome (MT) staining techniques, and electron microscopy analysis. Kidney cyclooxygenase-2 (COX-2), protein 53 (p53), and tumor necrosis factor-α (TNF-α) were detected by immunohistochemical staining techniques. Additionally, bioindicators of oxidative stress and antioxidant defense systems were identified in kidney tissue.
UNASSIGNED: In CCl4-injected rats, serum creatinine, urea, and uric acid levels significantly increased, as did renal lipid peroxidation (LPO), while superoxide dismutase, glutathione peroxidase (GPx), glutathione (GSH) transferase, and GSH levels significantly dropped in the kidneys. Histologically, the kidneys displayed a wide range of structural abnormalities, such as glomerular shrinkage, tubular dilations, inflammatory leukocytic infiltration, fibroblast proliferation, and elevated collagen content. Inflammatory cytokines like COX-2 and TNF-α as well as the pro-apoptotic mediator p53 were considerably upregulated. Treatment of BM-MSCs from mice and rats with CCl4-injected rats considerably reduced the previously noted abnormalities.
UNASSIGNED: By boosting antioxidant defense and reducing apoptosis and inflammation, BM-MSCs from mice and rats were able to enhance kidney function and histological integrity in rats that had received CCl4 injections.

UNASSIGNED: Cisplatin (Cis) is potent chemotherapy used to treating already many different types of cancer; however, it is found to correlate with nephrotoxicity and other adverse health consequences. Thymoquinone (TQ) is an antioxidant and anti-inflammatory molecule that may defend against the consequences of different chemotherapies. Thymoquinone uses, although, are negatively impacted by its weak solubility and inadequate biological availability.
UNASSIGNED: This investigation examined the efficacy of a new nanoparticle (NP) absorbing TQ in an Ehrlich Ascites Carcinoma (EAC) mice model to address its low solubility, enhance its bioavailability, and protect against Cis-induced nephrotoxicity.
UNASSIGNED: Following 4 treatment groups were included in this research: (1) control, (2) EAC, (3) EAC + Cis + Thymoquinone nanoparticle (TQ-NP) treated, and (4) EAC + Cis-treated.
UNASSIGNED: The study revealed that TQ-NP was efficacious in avoiding Cis-induced kidney problems in EAC mice, as well as restoring kidney function and pathology. Thymoquinone nanoparticle considerably reduced Cis-induced oxidative damage in renal tissue by augmenting antioxidant levels. According to tumor weight and histological investigation results, TQ-NP did not impair Cis\'s anticancer efficacy.
UNASSIGNED: Thymoquinone nanoparticle might be used as a potential drug along with Cis anticancer therapy to reduce nephrotoxicity and other side effects while maintaining Cis anticancer properties.
UNASSIGNED: Le cisplatine (CIS) est un puissant agent chimiothérapeutique utilisé pour le traitement de nombreux types de cancers. Le cisplatine est cependant corrélé à de la néphrotoxicité et à d’autres conséquences néfastes pour la santé. La thymoquinone (TQ) est une molécule antioxydante et anti-inflammatoire qui peut protéger contre les effets néfastes de différents agents chimiothérapeutiques. Les faibles solubilité et biodisponibilité de la TQ limitent toutefois son utilisation.
UNASSIGNED: Un modèle de souris atteintes d’un carcinome ascitique d’Ehrlich (souris EAC) a servi à vérifier l’efficacité d’une nouvelle nanoparticule (NP) absorbant la TQ pour remédier aux faibles solubilité et biodisponibilité de la TQ et protéger contre la néphrotoxicité induite par le CIS.
UNASSIGNED: Les quatre groupes suivants ont été examinés: i) témoin; ii) souris EAC; iii) souris EAC traitées par CIS + TQ-NP (thymoquinone-nanoparticule); iv) souris EAC traitées par CIS.
UNASSIGNED: L’étude a révélé que la TQ-NP était efficace pour éviter les problèmes rénaux induits par le CIS chez les souris EAC, de même que pour restaurer la fonction rénale et soigner la pathologie. En augmentant les niveaux d’antioxydants, la TQ-NP a considérablement réduit les dommages oxydatifs induits par le CIS dans le tissu rénal. Selon le poids des tumeurs et les résultats de l’étude histologique, la TQ-NP n’a pas altéré l’efficacité anticancéreuse du CIS.
UNASSIGNED: La TQ-NP pourrait potentiellement être utilisée avec le traitement anticancéreux par CIS afin de réduire la néphrotoxicité et les autres effets secondaires, sans altérer les propriétés anticancer du CIS.

[177Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-3H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities.

Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46-72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.

It has been estimated that nearly 80% of anticancer drug-treated patients receive potentially nephrotoxic drugs, while the kidneys play a central role in the excretion of anticancer drugs. Nephrotoxicity has long been a serious complication that hampers the effectiveness of cancer treatment and continues to influence both mortality and length of hospitalization among cancer patients exposed to either conventional cytotoxic agents or targeted therapies. Kidney injury arising from anticancer drugs tends to be associated with preexisting comorbidities, advanced cancer stage, and the use of concomitant non-chemotherapeutic nephrotoxic drugs. Despite the prevalence and impact of kidney injury on therapeutic outcomes, the field is sorely lacking in an understanding of the mechanisms driving cancer drug-induced renal pathophysiology, resulting in quite limited and largely ineffective management of anticancer drug-induced nephrotoxicity. Consequently, there is a clear imperative for understanding the basis for nephrotoxic manifestations of anticancer agents for the successful management of kidney injury by these drugs. This article provides an overview of current preclinical research on the nephrotoxicity of cancer treatments and highlights prospective approaches to mitigate cancer therapy-related renal toxicity.

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.

One-dimensional (1D) nanomaterials are widely used in different fields, and the increased application of 1D nanomaterials has drawn concerns about their unknown toxicity. 1D titanium oxide (TiO2) nanomaterials in different crystal phases are commonly applied in environmental remediation and solar energy conversion fields, but these materials pose a threat to human health, especially to the kidneys, an organ with abundant blood flow. To systematically evaluate the cytotoxicity to the kidneys, TiO2 nanofibers with TiO2(B), anatase, and rutile phases, as well as nanorods with anatase and rutile phases were synthesized and added to the culture medium of HK2 cells. Cell counting kit-8 assay, 2\',7\'-dichlorofluorescin diacetate assay, Hoechst 33342 staining experiments, and quantitative real-time reverse transcription polymerase chain reaction tests were used to explore the renal effects of the as-prepared TiO2 nanomaterials in the short term or long term. In the short-term evaluation, all the added TiO2 nanomaterials were toxic to HK2 cells, and the cytotoxicity was dose-dependent. Rutile TiO2 can widely attach to the cell surface and displays the most serious cell-killing and proapoptotic ability, while anatase induces the most serious oxidative stress. In long-term evaluation, all the as-prepared TiO2 nanomaterials led to epithelial mesenchymal transition (EMT), a mechanism of renal fibrosis. Consistent with the short-term results, rutile induced the most serious EMT. This study indicated that the renal toxicity of 1D TiO2 nanomaterials is crystal phase-dependent and that rutile induced the most significant renal cell injury. Oxidative stress is a crucial but not the only contributor to the renal toxicity of TiO2 nanomaterials in the short term.

Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and β-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients.

Cylindrospermopsin (CYN) has been involved in cases of poisoning in humans following ingestion. Studies have demonstrated that the kidney is the most affected organ. CYN exposure leads to low-molecular-weight proteinuria and increased excretions of the tubular enzymes in mice, suggesting the damage caused by CYN is mainly tubular. However, the mechanism involved in CYN nephrotoxicity remains unknown. Thus, in order to evaluate the effects of CYN exposure (0.1, 0.5 and 1.0 μg/mL) on tubular renal cells LLC-PK1 distinct mechanisms were analyzed by assessing cell death using flow cytometry, albumin uptake by fluorescence analysis, Na+/K+-ATPase activity by a colorimetric method, RT-qPCR of genes related to tubular transport and function as well as internalization of CYN by ELISA. In this study, CYN was found to induce necrosis in all concentrations. CYN also decreased albumin uptake as well as downregulated megalin and dab2 expression, both proteins involved in albumin endocytosis process. Moreover, CYN appears to be internalized by renal tubular cells through a receptor-mediated endocytosis. Finally, the present study demonstrates that CYN is responsible for disrupting tubular cell transport and function in LLC-PK1 cells.

Glutathione peroxidases (Gpxs) play vital roles in elimination of hydroperoxide and other reactive oxygen species through catalyzing reduced glutathione to protect from oxidative stress caused by heavy metals such as lead. Among the family of Gpxs, Gpx3 is the only extracellular enzyme synthesized in the kidney and actively secreted into the plasma. This study investigated mechanisms of lead-induced GPx3 inactivation both at the animal and molecular levels. Six-week-old mice were randomly divided into 4 groups, and exposed to different lead concentrations (0, 1, 2 and 4 g/L) in their drinking water for 4 weeks. Contents of GPx3 in blood serum were tested by enzyme-linked immunosorbent assay (ELISA) and the mRNA levels of Gpx3 in mice nephrocytes were determined by quantitative real-time PCR (qPCR), both of which showed significantly inhibited at higher lead concentrations accompanied by the decreased Gpx3 activities and the elevated levels of malondialdehyde (MDA) in nephrocytes, which indicated that lead could induce strongly oxidative stress through affecting Gpx3 function. So we further investigated molecular mechanisms of GPx3 inactivation caused by lead with multiple spectroscopic techniques, isothermal titration calorimetry (ITC) and molecular docking studies in vitro. Results showed that lead statically quenched GPx3 fluorescence by tightly binding to the structural domain of GPx3 in a 3:1 ratio with high binding affinity (K = 3.1(±0.087) × 107 mol-1). Further investigation of the conformation of GPx3 by UV-visible spectroscopy and circular dichroism (CD) spectroscopy indicated that lead changed the secondary structure of GPx3 by loosening the GPx3 skeleton and decreasing the hydrophobicity around tryptophan residues. This work proved in vivo and in vitro experiments that lead could induce oxidative stress in mice nephrocytes by interacting with GPx3.