Induced Kidney Injury Research Articles

Integrated analysis of transcriptome-wide m6A methylation in a Cd-induced kidney injury rat model

BackgroundAccumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in a variety of diseases. However, the specific functions of m6A in CdCl2-induced kidney injury remain unclear. ObjectiveHere, we investigate a transcriptome-wide map of m6A modifications and explore the effects of m6A on Cd-induced kidney injury. Materials and methodsThe rat kidney injury model was constructed by subcutaneous injection of CdCl2 (0.5, 1.0, and 2.0 mg/kg). The m6A levels were measured by colorimetry. The level of expression of m6A-related enzymes were detected by reverse transcription quantitative real-time PCR analysis. Transcriptome-wide m6A methylome in CdCl2 (2.0 mg/kg) and the control group were profiled by methylated RNA immunoprecipitation sequencing (MeRIP-seq). Subsequently, the sequencing data were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), while gene set enrichment analysis (GSEA) confirmed the functional enrichment pathways of sequencing genes. In addition, a protein-protein interaction (PPI) network was applied to select hub genes. ResultsThe levels of m6A and m6A regulators (METTL3, METTL14, WTAP, YTHDF2) were significantly increased in CdCl2 groups. We identified a total of 2615 differentially expressed m6A peaks, 868 differentially expressed genes and 200 genes with significant changes in both m6A modification and gene expression levels. GO, KEGG, and GSEA analyses indicated that these genes were mainly enriched in inflammation and metabolism-related pathways such as in IL-17 signaling and fatty acid metabolism. According the result of the conjoint analysis, we identified the top ten hub genes (Fos, Hsp90aa1, Gata3, Fcer1g, Cftr, Cspg4, Atf3, Cdkn1a, Ptgs2, and Npy) which may be regulated by m6A and involve in CdCl2-induced kidney damage. ConclusionThis study established a m6A transcriptional map in a CdCl2-induced kidney injury model and suggested that m6A may affect CdCl2 induced kidney injury via regulated the inflammation and metabolism related gene.

Di(2-ethylhexyl) phthalate mediates oxidative stress and activates p38MAPK/NF-kB to exacerbate diabetes-induced kidney injury in vitro and in vivo models.

Plasticizer di(2-ethylhexyl) phthalate (DEHP) is employed to make polyethylene polymers. Some studies in epidemiology and toxicology have shown that DEHP exposure over an extended period may be hazardous to the body, including nephrotoxicity, and aggravate kidney damage in the context of underlying disease. However, studies on the toxicity of DEHP in diabetes-induced kidney injury have been rarely reported. Using a high-fat diet (HFD) and streptozotocin (STZ, 35mg/kg)-induced kidney injury in mice exposed to various daily DEHP dosages, we explored the impacts of DEHP on diabetes-induced kidney injury. We discovered that DEHP exposure significantly promoted the renal inflammatory response and oxidative stress in mice, with increased P-p38 and P-p65 protein levels and exacerbated the loss of podocin. The same findings were observed in vitro after stimulation of podocytes with high glucose (30mmol/L) and exposure to DEHP. Our results suggest that DEHP exacerbates diabetes-induced kidney injury by mediating oxidative stress and activating p38MAPK/NF-κB.

PD17-03 REDOX IMBALANCE AND MAPK ACTIVATION MEDIATES PNEUMOPERITONEUM-INDUCED KIDNEY INJURY DURING MINIMALLY INVASIVE SURGERY

You have accessJournal of UrologyCME1 Apr 2023PD17-03 REDOX IMBALANCE AND MAPK ACTIVATION MEDIATES PNEUMOPERITONEUM-INDUCED KIDNEY INJURY DURING MINIMALLY INVASIVE SURGERY Charbel Chalouhy, Nassim Fares, Youakim Saliba, Pedro Maria, Ahmed Aboumoouhamed, Marwan Kassis, Alexander Small, and Justin Loloi Charbel ChalouhyCharbel Chalouhy More articles by this author , Nassim FaresNassim Fares More articles by this author , Youakim SalibaYouakim Saliba More articles by this author , Pedro MariaPedro Maria More articles by this author , Ahmed AboumoouhamedAhmed Aboumoouhamed More articles by this author , Marwan KassisMarwan Kassis More articles by this author , Alexander SmallAlexander Small More articles by this author , and Justin LoloiJustin Loloi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Given the widespread use of laparoscopic and robotic surgeries, the effects of pneumoperitoneum (PNP) during minimally invasive surgery on kidney function become of great interest. PNP during laparoscopy causes transient renal functional impairment via various detrimental factors, such as oxidative stress. We, therefore, investigated the oxidative signaling pathways inherent to PNP-induced kidney injury. METHODS: PNP was established at an intraperitoneal CO 2 pressure of 12 mmHg in Wistar rats randomly allocated into three groups: Sham, PNP1, and PNP24. PNP1 and PNP24 animals were sacrificed at one and 24 hours following PNP deflation, respectively. Renal histology, function, redox status, and signaling pathways were assessed. RESULTS: PNP induced kidney injury and dysfunction with altered KIM-1 profile. Both expression and activity of antioxidant (CAT, SOD1/2) and oxidant (NOS3) enzymes, lipid peroxidation, and renal RNA/DNA damage biomarkers revealed redox imbalance after PNP, with an excess H2O2 production. Moreover, the antioxidant gene regulators FoxO3a and Nrf2 were activated. Nevertheless, PNP had no effect on the cellular apoptotic pathways Bcl2, Bid, Caspase 3 and 8. Finally, PNP stimulated the p38 and JNK mitogen-activated protein kinase (MAPK) pathways in the kidney. CONCLUSIONS: Our results demonstrate for the first time that PNP induces acute kidney injury due to renal redox imbalance linked to MAPK activation. These insights may open the way for further investigation into the renal therapeutic impact of managing PNP-associated oxidative stress during robotic surgery and explore procedure-specific kidney function recovery patterns i.e. after robotic partial nephrectomy or robotic kidney transplant. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e495 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Charbel Chalouhy More articles by this author Nassim Fares More articles by this author Youakim Saliba More articles by this author Pedro Maria More articles by this author Ahmed Aboumoouhamed More articles by this author Marwan Kassis More articles by this author Alexander Small More articles by this author Justin Loloi More articles by this author Expand All Advertisement PDF downloadLoading ...

The microplastics exposure induce the kidney injury in mice revealed by RNA-seq

Microplastics (MPs) may pollute drinking water, accumulate in the food chain, and release toxic chemicals that may cause a variety of diseases. The detrimental effects of MPs on kidney injury and fibrosis under long-term accumulation have not been fully documented. In this study, mice were exposed to MPs with three different diameters (80 nm, 0.5 µm, and 5 µm) to investigate the detrimental influences of MPs on the kidney. The results showed that MPs of different diameters caused varying degrees of injury to the murine kidney. MPs exposure can induce an inflammatory response, oxidative stress, and cell apoptosis in the kidney and induce kidney injury, which ultimately promotes kidney fibrosis. Furthermore, transcriptome data revealed that chronic exposure to MPs could alter the expressions of multiple genes related to immune response (80 nm) and circadian rhythm (0.5 µm, and 5 µm). Overall, our data provide new evidence and potential research for investigating the harm of MPs to kidney of mammals and even humans.

Protocatechuic acid ameliorates lipopolysaccharide-induced kidney damage in mice via downregulation of TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways.

Acute kidney injury (AKI) is a very critical cause of death in the whole world. Lipopolysaccharide (LPS) induces kidney damage by activating various deleterious inflammatory and oxidative pathways. Protocatechuic acid, a natural phenolic compound, has shown to exert beneficial effects against oxidative and inflammatory responses. The study aimed to clarify the nephroprotective activity of protocatechuic acid in LPS-induced acute kidney damage in mice. Forty male Swiss mice were allocated in four groups as follows: normal control group; LPS (250 μg/kg, ip)-induced kidney injury group; LPS-injected mice treated with protocatechuic acid (15 mg/kg, po), and LPS-injected mice treated with protocatechuic acid (30 mg/kg, po). Significant toll-like receptor 4 (TLR-4)-mediated activation of IKBKB/NF-κB and MAPK/Erk/COX-2 inflammatory pathways has been observed in kidneys of mice treated with LPS. Oxidative stress was revealed by inhibition of total antioxidant capacity, catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and NAD(P)H quinone oxidoreductase (NQO1) enzyme along with increased nitric oxide level. In parallel, focal inflammatory effects were shown in between the tubules and glomeruli as well as in the perivascular dilated blood vessels at the cortex affecting the normal morphology of the kidney tissues of LPS-treated mice. However, treatment with protocatechuic acid reduced LPS-induced changes in the aforementioned parameters and restored normal histological features of the affected tissues. In conclusion, our study uncovered that protocatechuic acid has nephroprotective effects in mice with AKI through opposing different inflammatory and oxidative cascades.

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.

Our understanding of how global changes in cellular metabolism contribute to human kidney disease remains incompletely understood. Here we show that nicotinamide adenine dinucleotide (NAD+) deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development. Using unbiased global metabolomics in healthy and diseased human kidneys, we identify NAD+ deficiency as a disease signature. Furthermore using models of cisplatin- or ischaemia-reperfusion induced kidney injury in male mice we observed NAD+ depletion Supplemental nicotinamide riboside or nicotinamide mononucleotide restores NAD+ levels and improved kidney function. We find that cisplatin exposure causes cytosolic leakage of mitochondrial RNA (mtRNA) and activation of the cytosolic pattern recognition receptor retinoic acid-inducible gene I (RIG-I), both of which can be ameliorated by restoring NAD+. Male mice with RIG-I knock-out (KO) are protected from cisplatin-induced kidney disease. In summary, we demonstrate that the cytosolic release of mtRNA and RIG-I activation is an NAD+-sensitive mechanism contributing to kidney disease.

Salidroside attenuates LPS-induced kidney injury through activation of SIRT1/Nrf2 pathway.

Salidroside (SAL) is an anti-inflammatory, antioxidant, anticancer, neuroprotective, and renal protective active ingredient extracted from the Chinese herb. Rhodiola Rosea. However, the role of SAL in kidney injury has not yet been elucidated. The study investigates SAL's protective effect and mechanism in lipopolysaccharide (LPS)-induced kidney injury. Male C57BL/6 wild-type mice (6-8weeks old) were intraperitoneally injected with 10mg/kg LPS for 24h and SAL (50mg/kg) 2h before the LPS injection. Biochemical and TUNNEL staining assay analyses were carried out to assess kidney injury. The Elisa assay analyzed the mRNA expression of NGAL and KIM-1. RT-qPCR and Western blotting measured the mRNA and protein expression of HO-1, NQO1, Beclin1, P62, SIRT1, Nrf2, and PNCA, respectively. Our study found that mice co-treated with SAL had significantly reduced blood urea nitrogen (BUN), serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) levels in serum of LPS-induced mice. SAL cotreatment potentially decreased the apoptosis rate of kidney tissue and podocytes induced by LPS. SAL significantly reduced the content of malondialdehyde (MDA) and increased superoxide dismutase (SOD) in LPS-treated mice. Autophagy-related proteins Beclin-1 increased but decreased P62 protein expression by cotreatment of SAL in LPS-injected mice. SAL enhanced the Sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in LPS-induced kidney tissues. Our results speculate that SAL protects against LPS-induced kidney injury through activation of the SIRT1/Nrf2 pathway.

First Author Highlights

AnnouncementFirst Author HighlightsPublished Online:17 Mar 2023https://doi.org/10.1152/ajprenal.2023.324.3.AUMoreSectionsPDF (404 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat MOLLY BINGHAMSystems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United StatesFigure 1.Molly BinghamDownload figureDownload PowerPointMolly Bingham is a Postbaccalaureate Research Fellow at the National Cancer Institute. As an intern in the National Institute of Health’s 2021 Biomedical Engineering Summer Internship Program (led by Dr. Robert Lutz), she was mentored by Dr. Mark Knepper and studied circadian changes in gene expression in the kidney proximal tubule. Currently, Molly is investigating the tumor microenvironment in lung cancer under the mentorship of Dr. Chen Zhao. She hopes to pursue a career as a physician-scientist. When not in the laboratory or analyzing data, Molly enjoys cooking and spending time outdoors [Photo: Fig. 1].https://doi.org/10.1152/ajprenal.00231.2022JEROEN H. F. DE BAAIJDepartment of Physiology, Radboud University Medical Center, Nijmegen, The NetherlandsFigure 2.Jeroen de BaaijDownload figureDownload PowerPointJeroen de Baaij is an Associate Professor in renal physiology at the Radboud University Medical Center in Nijmegen, The Netherlands. His research focusses on the identification and characterization of new genes involved in renal magnesium reabsorption. Using a wide range of molecular, cellular, and physiological techniques, he examines new genes or new regulatory pathways in magnesium (re)absorption in the kidney. In his spare time, he writes about art and visits museums [Photo: Fig. 2].https://doi.org/10.1152/ajprenal.00298.2022KYLE DICKINSONDivision of Experimental Medicine, McGill University, Montreal, Quebec, CanadaFigure 3.Kyle DickinsonDownload figureDownload PowerPointKyle Dickinson is a researcher and laboratory manager in Dr. Julia Burnier’s laboratory at McGill University. He completed his PhD in Dr. Paul Goodyer’s laboratory in Experimental Medicine at McGill University. During his PhD, his research focused on understanding key signalling and DNA damage response pathways active in nephron progenitor cells during kidney development. His current research focuses on using liquid biopsy for cancer detection and monitoring treatment responses. Away from the laboratory bench, he enjoys sports, video games, and horror movies [Photo: Fig. 3].https://doi.org/10.1152/ajprenal.00207.2022MACKENZIE KUIDepartment of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United StatesFigure 4.Mackenzie KuiDownload figureDownload PowerPointMackenzie Kui is currently a third-year PhD student in Jennifer Pluznick’s laboratory at Johns Hopkins University. Mackenzie earned his Bachelor’s degree from the University of California-Santa Barbara, where he studied germline stem cell longevity in Drosophila diapause. After graduating, he worked as a Research Associate at City of Hope and then later at Oncovalent Therapeutics in small molecule discovery. Outside of the laboratory, Mackenzie enjoys climbing, volleyball, and swing dancing [Photo: Fig. 4].https://doi.org/10.1152/ajprenal.00272.2022ANDREW ORWICKDepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KentuckyFigure 5.Andrew OrwickDownload figureDownload PowerPointAndrew Orwick is a PhD student in the Department of Pharmacology and Toxicology at the University of Louisville, mentored by Dr. Leah Siskind. He earned his PharmD from Sullivan University and practiced as a pharmacist for a number of years before deciding to go back to graduate school to obtain a PhD in the biomedical sciences. His PhD studies in chemotherapy-induced nephrotoxicity are supported by a National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases F31 predoctoral fellowship. Andrew hopes to have his own research laboratory in academia one day. In his spare time, he enjoys playing soccer and spending time with his wife and two daughters [Photo: Fig. 5].https://doi.org/10.1152/ajprenal.00317.2022This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformation Related ArticlesCircadian gene expression in mouse renal proximal tubule 01 Mar 2023American Journal of Physiology-Renal PhysiologyMagnesium reabsorption in the kidney 17 Feb 2023American Journal of Physiology-Renal PhysiologyWT1 regulates expression of DNA repair gene Neil3 during nephrogenesis 17 Feb 2023American Journal of Physiology-Renal PhysiologyThe transcription factor Foxi1 promotes expression of V-ATPase and Gpr116 in M-1 cells 17 Feb 2023American Journal of Physiology-Renal PhysiologyLung cancer-kidney cross talk induces kidney injury, interstitial fibrosis, and enhances cisplatin-induced nephrotoxicity 01 Mar 2023American Journal of Physiology-Renal Physiology More from this issue > Volume 324Issue 3March 2023Pages i-ii Crossmark Copyright & PermissionsCopyright © 2023 the American Physiological Society.https://doi.org/10.1152/ajprenal.2023.324.3.AUPubMed36929919History Published online 17 March 2023 Published in print 1 March 2023 Metrics

Abstract Number ‐ 254: Yield of CTA in Patients over 50 with Brain Hemorrhages at Sites Typical for Hypertension

Introduction Approximately 10%–15% of acute strokes are spontaneous, nontraumatic intraparenchymal cerebral hemorrhage (IPH). Hypertension (HTN), amyloid angiopathy, or impaired coagulation cause most spontaneous IPHs, in which case the CTA is unlikely to identify an underlying vascular lesion. Prior investigators have identified clinical and non‐contrast CT (NCCT) features that increase the likelihood of identifying a vascular etiology for an IPH, including younger age (< 40–50), absence of hypertension, and presence of subarachnoid (SAH) or intraventricular hemorrhage (IVH). Findings from earlier studies of patients with IPH suggested that older age, HTN, together with certain locations (basal ganglia, thalamus, cerebellum, and pons) could reliably exclude IPH patients with underlying lesions. We aimed to assess the yield of CTA, a costly study with risks of radiation, contrast induced renal injury and death, in identifying vascular lesions in this group. Methods This retrospective study involved reviewing medical records of all patients admitted to Carilion RMH hospital for brain hemorrhage during the period 2008–2020, inclusive. Patients were considered if they were over 50 year of age, had HTN (and/or left ventricular hypertrophy on electrocardiograms or echocardiograpy) and IPH in the thalamus, basal ganglia, cerebellum or pons. Patients with SAH, lobar IPH, traumatic IPH, pure IVH, and patients with known vascular lesions were excluded. Imaging of all patients was reviewed with attention to finding CTAs showing vascular lesions that might have caused of the recent symptomatic IPH (arteriovenous malformations, aneurysms, venous anomalies and dural venous sinus thrombosis). Small saccular aneurysms at remote sites were not considered relevant, nor were intra‐ or extracranial stenoses. Results A total of (446) charts were reviewed, of which 143 met the inclusion criteria (94 males and 49 females). Family history was positive for cerebral aneurysm in one patient and Alzheimer’s with brain hemorrhage in another. Twenty‐six patients were on anticoagulation: 10 on NOAC, 14 on Warfarin (INR was < 2 in 8, 2–3 in 5, and >3 in only one patient). One was on subcutaneous heparin (PTT was 53). No other patient had major coagulation abnormalities; only 5 patients had platelets count < 100K, the lowest was 62K. CTA was negative for underlying vascular lesion at the site of bleeding in all 143 patients, confidence interval 2.6% using Confidence intervals for proportions, using Wilson’s method for proportions. Conclusions In patients over 50 year of age with evidence of hypertension, and ICH in the basal ganglia, thalamus, brain stem and cerebellum; the diagnostic yield of CTA is negligible. Performing this study routinely in the evaluation of these patient increases health care costs, and exposes patients to the risks of unnecessary radiation, contrast induced kidney injury and death. We recommend against the routine use of CTA in patients meeting the above criteria.

Investigation of the nephrotoxicity of 2,6-dichloro-1,4-benzoquinone disinfection by-product in mice through a 28-day toxicity test

In recent years, 2,6-dichloro-1,4-benzoquinone (DCBQ) has become an emerging water disinfection by-product and widely distributed in disinfected water. Although kidney is a potential target of DCBQ, a systematic study of the in vivo nephrotoxicity of DCBQ is rare. In this study, a 28-day oral toxicity test was used to assess the nephrotoxic effects of DCBQ on mice. And the potential mechanisms of nephrotoxicity induced by DCBQ were explored through inflammation, oxidative stress, apoptosis and gut microbiota. The results showed that the kidney indexes of mice were not altered in DCBQ-exposed group in comparison with the control group. The histopathological investigation revealed that DCBQ caused swollen of renal tube, destruction of the renal structure, and infiltration of inflammatory cell in kidney. DCBQ has induced oxidative damage in kidney, as the observation of the increase of the renal superoxide dismutase (SOD) and catalase (CAT) activity. Also, DCBQ has triggered the inflammatory response in kidney through the increased expression of IL-1β, NF-κB and iNOS. Moreover, DCBQ has activated the apoptosis pathway, as indicated by the increased mRNA expression of Caspase-3 and Caspase-9. We eventually found an association between gut microbiota and nephrotoxic variables, demonstrating the importance of gut-kidney axis in DCBQ toxicity. Our results suggested that exposure to DCBQ in disinfected water might be a risk factor for kidney and provided novel insights into the underlying mechanisms of DCBQ–induced kidney injury, contributing to better interpretation of the health impact of the environmentally emerging contaminant DCBQ.

Kluyveromyces marxianus Ameliorates High-Fat-Diet-Induced Kidney Injury by Affecting Gut Microbiota and TLR4/NF-κB Pathway in a Mouse Model

Objectives. The effects of Kluyveromyces marxianus on high-fat diet- (HFD-) induced kidney injury (KI) were explored. Methods. HFD-induced KI model was established using male C57BL/6 mice and treated with K. marxianus JLU-1016 and acid-resistant (AR) strain JLU-1016A. Glucose tolerance was evaluated via an oral glucose tolerance test (OGTT). KI was measured using Hematoxylin and Eosin (H&E) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. The chemical indexes were analyzed, including lipid profiles, inflammatory cytokines, and creatinine. The levels of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) or phospho-NF-κB p65 (Ser536) and alpha inhibitor of NF-κB (IκBα) were measured using qPCR and Western blot. The gut microbiota was sequenced using high-throughput sequencing. Results. HFD induction increased OGTT value, KI severity, oxidative stress, inflammatory cytokines, oxidative stress, apoptotic rate, creatinine levels, and the expression of TLR4/NF-κB, phospho-NF-κB p65 (Ser536), and IκBα deteriorated lipid profiles ( P < 0.05 ) and reduced gut microbiota abundance. K. marxianus treatment ameliorated HFD-induced metabolic disorders and reversed these parameters ( P < 0.05 ). Compared with the control, HFD induction increased the proportion of Firmicutes but reduced the proportion of Bacteroidetes and Lactobacillus. K. marxianus JLU-1016 and AR strain JLU-1016A treatments improved gut microbiota by reducing the proportion of Firmicutes and increasing the proportion of Bacteroidetes and Lactobacillus in the KI model ( P < 0.0001 ). Helicobacter has been identified with many infectious diseases and was increased after HFD induction and inhibited after K. marxianus JLU-1016 and AR strain JLU-1016A treatments. The strain JLU-1016A exhibited better results possibly with acid-tolerance properties to pass through an acidic environment of the stomach. Conclusions. K. marxianus may have a beneficial effect on KI by improving gut microbiota and inhibiting TLR4/NF-κB pathway activation.

Mitochondrial and NAD+ metabolism predict recovery from acute kidney injury in a diverse mouse population.

Acute kidney failure and chronic kidney disease are global health issues steadily rising in incidence and prevalence. Animal models on a single genetic background have so far failed to recapitulate the clinical presentation of human nephropathies. Here, we used a simple model of folic acid-induced kidney injury in 7 highly diverse mouse strains. We measured plasma and urine parameters, as well as renal histopathology and mRNA expression data, at 1, 2, and 6 weeks after injury, covering the early recovery and long-term remission. We observed an extensive strain-specific response ranging from complete resistance of the CAST/EiJ to high sensitivity of the C57BL/6J, DBA/2J, and PWK/PhJ strains. In susceptible strains, the severe early kidney injury was accompanied by the induction of mitochondrial stress response (MSR) genes and the attenuation of NAD+ synthesis pathways. This is associated with delayed healing and a prolonged inflammatory and adaptive immune response 6 weeks after insult, heralding a transition to chronic kidney disease. Through a thorough comparison of the transcriptomic response in mouse and human disease, we show that critical metabolic gene alterations were shared across species, and we highlight the PWK/PhJ strain as an emergent model of transition from acute kidney injury to chronic disease.

Lung cancer-kidney cross talk induces kidney injury, interstitial fibrosis, and enhances cisplatin-induced nephrotoxicity.

Patients with cancer represent a unique patient population with increased susceptibility to kidney disease. Drug-induced acute kidney injury (AKI) in patients with cancer is a common problem. Cisplatin is a highly effective treatment used in many solid-organ cancers and causes AKI in 30% of patients, increasing the risk of chronic kidney disease development. Most preclinical cisplatin toxicity studies have been completed in mice without cancer. We believe that the physiology of patients with cancer is not adequately represented in preclinical models, and the objective of this study was to determine how lung cancer will alter the nephrotoxicity of cisplatin. A genetically engineered mouse model and a syngeneic xenograft model of lung cancer were used. Mice were divided into the following four groups: 1) noncancer/vehicle, 2) noncancer/cisplatin, 3) cancer/vehicle, and 4) cancer/cisplatin. Mice were administered cisplatin via intraperitoneal injection once a week for 4 wk. Animals were euthanized 72 h following their final cisplatin injection. Mice with lung cancer had increased renal toxicity, injury, and fibrosis following repeated low doses of cisplatin. In addition, lung cancer alone induced kidney injury and fibrosis in the kidney before cisplatin treatment. In conclusion, this is the first study that we are aware of that assesses the impact of cancer on the kidney in conjunction with the nephrotoxicity of cisplatin. We believe that cancer is providing the first hit to the kidney and the subsequent damage from repeated doses of cisplatin becomes unsurmountable, leading to AKI and progression to chronic kidney disease.NEW & NOTEWORTHY Patients with cancer have impaired kidney function and increased susceptibility to nephrotoxic agents. Cisplatin is a commonly used chemotherapeutic with nephrotoxicity as the dose-limiting side effect. Cisplatin nephrotoxicity is almost exclusively studied in mice without cancer. Our current preclinical models do not adequately represent the complexity of patients with cancer. This study demonstrates increased renal toxicity, injury, and fibrosis in mice with lung cancer, which is exacerbated with cisplatin treatment. These results highlight the necessity of using preclinical models that more accurately capture the altered physiology of patients with cancer treated with cisplatin.

Nephrotoxicity assessment of Esculentoside A using human-induced pluripotent stem cell-derived organoids.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI). A major obstacle in predicting AKI is the lack of a comprehensive experimental model that mimics stable and physiologically relevant kidney functions and accurately reflects the changes a drug induces. Organoids derived from human-induced pluripotent stem cells (iPSCs) are promising models because of their reproducibility and similarity to the in vivo conditions. In this study, Esculentoside A, the triterpene saponin with the highest concentration isolated from the root of Phytolacca acinose Roxb., was used to induce kidney injury models in vivo and kidney organoids. Esculentoside A induced AKI in mice, together with pathological changes and enhanced apoptosis. Moreover, Esculentoside A damaged podocytes and proximal tubular endothelial cells in kidney organoids in a similar way as in vivo. We also found that treatment with 60 μM Esculentoside A induced the known biomarkers of kidney damage and inflammatory cytokines (such as kidney injury molecule (KIM-1), β2-microglobulin (β2-M), and cystatin C (CysC)) in the organoids, in which activation of Cleaved Caspase-3 was involved, possibly due to lowered mitochondrial membrane potential. In summary, this study strongly suggests using kidney organoids as a reliable platform to assess Chinese medicine-induced nephrotoxicity.

Elevated levels of biomarkers of oxidative stress and renal injury linked to nitrogenous flame retardants exposure in e-waste dismantling site: A case study in China

Nitrogenous flame retardants (NFRs) have aroused worldwide public concern as their nephrotoxic effect. However, knowledge regarding the pathogenesis mechanism of their exposure to induce kidney injury remains largely unknown. In this study, eight NFRs, four oxidative stress biomarkers (OSBs), and one kidney injury biomarker, namely neutrophil gelatinase-associated lipocalin (NGAL), were measured in urine specimens collected from residents living around e-waste disassembly and reference areas, representing two exposure scenarios. Significant higher concentrations of Σ8NFR (median: 70.6 vs. 33.8 μg/g Cre) and five biomarkers (124 vs. 97.4 μg/g Cre) were found in urines of populations living in e-waste site compared to those in the reference site (p < 0.05). Primary NFRs exhibited significant positive associations with OSBs and NGAL regardless of the population examined, implying that chronic NFRs exposure could induce oxidative stress and kidney damage. By using structure equation model, we found that oxidative stress, particularly DNA and RNA oxidation mediated 16.1% of the total effect of NFRs on NGAL in e-waste related people, but not on the general population. Overall, this study suggests long-term chronic exposure to NFRs can induce oxidative stress and renal injury in humans but the pathogenesis mode may be scenario-specific.

Hispidulin protective impact on sepsis induced acute kidney injury is mediated by regulation of AKT and NF-κB pathway

Sepsis-induced acute kidney injury is associated with inflammatory dysregulations within the kidney. This study aimed to explore the renal protective effect of hispidulin on suppressing the apoptosis rate, and inhibiting reactive oxygen species production and inflammatory response after cecal puncture (CLP) operation. In order to gain a deeper understanding of the relationship between sepsis and acute kidney injury, the CLP induced kidney injury animal model was established. The automated biochemical analyzer was used to measure the kidney function related biomarkers including serum cystatin C (ScysC), blood urea nitrogen (BUN), and serum creatinine (Scr). The pathological changes of damaged kidney tissues were detected by hematoxylin and eosin (H&amp;E) staining. The expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) were detected by their corresponding test kits and Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). The level of reactive oxygen species production-related protein including myeloperoxidase (MPO), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in kidney tissue from each group were quantized using Enzyme-linked immunosorbent assay (ELISA). The protein expression was measured using western blot and the apoptotic rate of kidney tissue was measured by terminal deoxynucleotidyl transferase Deoxyuridine Triphosphate (dUTP) nick end labeling (TUNEL) assay. Our results revealed that hispidulin has the protective ability in sepsis-induced acute kidney injury. The potential mechanism of hispidulin on sepsis-induced cell apoptosis, oxidative stress and inflammatory response was also investigated. Finally, our results highlighted that hispidulin exerted a protective effects on CLP-induced acute kidney injury by suppressing the protein kinase B (AKT) and Nuclear factor kappa B (NF-κB) signaling pathways. In summary, the current study provided a piece of novel evidence, that hispidulin can be explored as a potential drug in CLP-induced acute kidney injury by examining its effects on suppressed the oxidative stress, inflammatory responses, and apoptosis in kidney tissue.

DBP and BaP co-exposure induces kidney injury via promoting pyroptosis of renal tubular epithelial cells in rats

Dibutyl phthalate (DBP) and benzo(a)pyrene (BaP) are widespread environmental and foodborne contaminants that have detrimental effects on human health. Although people are often simultaneously exposed to DBP and BaP via the intake of polluted food and water, the combined effects on the kidney and potential mechanisms remain unclear. Hence, we treated rats with DBP and BaP for 90 days to investigate their effects on kidney histopathology and function. We also investigated the levels of paramount proteins and genes involved in pyroptosis and TLR4/NF-κB p65 signaling in the kidney. Our research showed that combined exposure to DBP and BaP triggered more severe histopathological and renal function abnormalities than in those exposed to DBP or BaP alone. Simultaneously, combined exposure to DBP and BaP enhanced the excretion of IL-1β and IL-18, along with the release of LDH in rat renal tubular epithelial cells (RTECs). Moreover, combined exposure to DBP and BaP increased the expression of pyroptosis marker molecules, including NLRP3, ASC, cleaved-Caspase-1, and GSDMD. Meanwhile, the combination of DBP and BaP activated TLR4/NF-κB signaling in the kidney. Taken together, the combined exposure to DBP and BaP causes more severe kidney injury than that caused by DBP or BaP exposure separately. In addition, pyroptosis of RTECs regulated by TLR4/NF-κB signaling may add to the kidney damage triggered by combined exposure to DBP and BaP.

Mancozeb induces nephrotoxicity by impairing the oxidative phosphorylation pathway: A transcriptome study

This study analyzed the mechanism underlying mancozeb (MCZ)-induced kidney injury by detecting kidney function indicators, combined with transcriptome and metabolome sequencing. Twenty mice were randomly assigned into two groups (control and MCZ groups) to explore the MCZ-induced kidney toxicity. The control group was gavaged with 0.2 mL of deionized water, and the MCZ group with 0.2 mL of 100 mg/kg MCZ for 30 days. The kidney structure of the MCZ group was damaged, with slight hyaline degeneration in the kidney tubular epithelial envelope. The creatinine (CRE) and uric acid (UA) were significantly increased in the MCZ group than in the control group. Moreover, the reactive oxygen species (ROS) significantly accumulated in the MCZ group kidneys. Compared to the control group, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were significantly decreased in the MCZ group, while the MDA content was substantially increased. The differentially expressed genes (DEGs) in the MCZ group were mainly enriched in the oxidative phosphorylation pathway. Besides, in the MCZ group, ndufs1 and ndufab1 genes were significantly up-regulated, while cox5b, ndufa5, and ndufa6 genes were significantly down-regulated, consistent with the PCR verification results. The metabolomic analysis identified cGMP-PKG signaling pathway of MCZ-induced nephrotoxicity, with Guanosine monophosphate and Adenosine 5′-monophosphate as the main altered metabolites. These results indicated that MCZ impairs the mice kidneys by obstructing the oxidative phosphorylation pathway, which increases oxidative stress in the kidneys, resulting in kidney injury.

The effect of lycopene on contrast-induced nephrotoxicity in diabetic patients undergoing coronary angiography

Introduction: Radiocontrast nephrotoxicity refers to one of the most prevalent and key complications in diabetic patients. Objectives: This study was aimed to investigate the therapeutic and protective effect of lycopene on contrast-induced nephrotoxicity (CIN) in diabetic patients undergoing coronary angiography. Patients and Methods: In this study, 113 patients who took lycopene with prevention of contrast induced kidney injury regime (lycopene group) or prevention of kidney injury regimen alone (regimen group) were investigated through medical records. Oral lycopene was administered 24 hours before to 72 hours after the angiography. Blood urea nitrogen (BUN), creatinine (Cr), and glomerular filtration rate (GFR) were assessed and recorded in a checklist. SPSS software was conducted for data analysis. Results: At the baseline, there was no significant difference between the mean of urea, Cr, and GFR (P&gt;0.05). However, after administration of lycopene, a significant difference between the mean BUN was observed among groups (P&lt;0.001), with lower rate in the patients taking oral lycopene. Although the mean Cr decreased after the administration of oral lycopene, no statistically significant difference was seen (P = 0.08). The mean GFR was not significant different between the two groups of regimen and lycopene (P=0.44). Conclusion: In patients with diabetes, taking lycopene for CIN may help improve some biochemical factors; nevertheless, its positive effect on the improvement of nephrotoxicity indices cannot be certainly determined.

Cross-Regulation between Autophagy and Apoptosis Induced by Vitamin E and Lactobacillus Plantarum through Beclin-1 Network.

Autophagy and apoptosis are two important regulatory mechanisms for how the body can respond to diseases. This study was designed to investigate the protective actions of vitamin E (Vit-E) and lactobacillus plantarum (Lac-B) against mercuric chloride (HgCl2)-induced kidney injury. Thirty albino rats were divided into five groups: group 1 served as the normal group; rats in group 2 received high doses of HgCl2; rats in groups 3, 4 and 5 were given Vit-E, Lac-B and the combination of Vit-E and Lac-B, respectively along with HgCl2 for two weeks. HgCl2 provoked renal injury, manifested by elevation in serum urea, urea nitrogen and creatinine. Kidney levels of oxidative stress and inflammation were markedly increased post HgCl2 administration. Moreover, HgCl2 significantly elevated the gene expression levels of VCAM-1 and cystatin C, while podocin was downregulated. Additionally, it markedly decreased the protein expression of Beclin-1 and Bcl-2. Histopathological examination revealed massive degeneration with congested blood vessels following HgCl2 administration. Treatment with Vit-E or/and Lac-B restored the normal levels of the previously mentioned parameters, as well as improved the morphology of kidney tissues. Both Vit-E and Lac-B provided a protective effect against HgCl2-induced kidney damage by regulating autophagy and apoptosis.