Search Results (306)

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

The efficient synthetic routes and evaluates cytotoxic profiles of denitroaristolochic acids II–V (DAA-II–V) were demonstrated in this study. Based on retrosynthetic analysis, a modular synthetic strategy was developed through Suzuki–Miyaura coupling, Wittig reaction, and bismuth triflate-catalyzed intramolecular Friedel–Crafts cyclization to efficiently construct the phenanthrene core. Process optimization significantly improved yields: aryl bromide intermediate A reached 50.8% yield via bromination refinement, while arylboronic ester intermediate B overcame selectivity limitations. Combining Darzens condensation with Wittig reaction enhanced throughput, achieving 88.4% yield in the key cyclization. Structures were confirmed by NMR and mass spectra. CCK-8 cytotoxicity assays in human renal proximal tubular epithelial cells revealed distinct toxicological profiles: DAA-III and DAA-IV exhibited IC₅₀ values of 371 μM and 515 μM, respectively, significantly higher than the nitro-containing prototype AA-I (270 μM), indicating that the absence of nitro group attenuates but does not eliminate toxicity, potentially via altered metabolic activation. DAA-II and DAA-V showed no detectable cytotoxicity within assay limits, suggesting reduced toxicological impact. Structure–activity analysis exhibited that the nitro group is not essential for cytotoxicity, with methoxy substituents exerting limited influence on potency. This challenges the conventional DNA adduct-dependent toxicity paradigm, implying alternative mechanisms like oxidative stress or mitochondrial dysfunction may mediate damage in denitro derivatives. These systematic findings provide new perspectives for AA analog research and a foundation for the rational use and safety assessment of Aristolochiaceae plants. Full article

Background and Clinical Significance: Although dietary supplements have often been deemed safe, some have been linked to drug-induced nephropathy due to their diverse ingredients. The aim of this report is to enhance clinical awareness of a novel and emerging cause of Fanconi syndrome due to red yeast rice supplements and to contribute new histopathological and clinical data. Case Presentation: We report two cases of renal dysfunction and Fanconi syndrome associated with the use of red yeast rice supplements. Both patients presented with renal impairment accompanied by elevated markers of tubular injury, hypouricemia, hypokalemia, and glucosuria, consistent with Fanconi syndrome. Following the discontinuation of the red yeast rice supplement and initiation of steroid therapy, Fanconi syndrome resolved, however, moderate renal dysfunction persisted. Urinary NGAL levels improved after treatment in both cases. KIM-1 normalized in one case but remained elevated in the other. Uromodulin recovery was complete in one case and partial in the other. Renal biopsy revealed mild tubulointerstitial nephritis, with notable shedding of proximal tubular epithelial cells. Immunohistochemical analysis demonstrated reduced expression of URAT-1, Na-K ATPase, and Na-Pi IIa in some tubules. Conclusions: These findings suggest that renal injury induced by red yeast rice supplements is mediated by direct proximal tubular necrosis caused by a harmful substance in the supplement, resulting in persistence of tubular dysfunction. Full article

Renal function refers to the combined actions of the glomerulus and tubular system to achieve homeostasis in bodily fluids. While the glomerulus is essential in the first step of urine formation through a coordinated filtration mechanism, the tubular system carries out active mechanisms of secretion and reabsorption of solutes and proteins using specific transporters in the epithelial cells. The assessment of renal function usually focuses on glomerular function, so the tubular function is often underestimated as a fundamental part of daily clinical practice. Therefore, it is essential to properly understand the tubular physiological mechanisms and their clinical association with prevalent human pathologies. This review discusses the primary solutes handled by the kidneys, including glucose, amino acids, sodium, potassium, calcium, phosphate, citrate, magnesium and uric acid. Additionally, it emphasizes the significance of physicochemical characteristics of urine, such as pH and osmolarity. The use of a concise methodology for the comprehensive assessment of urine should be strengthened in the basic training of nephrologists when dealing with problems such as water and electrolyte balance disorders, acid-base disorders, and harmful effects of commonly used drugs such as chemotherapy, antibiotics, or diuretics to avoid isolated replacement of the solute without carrying out comprehensive approaches, which can lead to potentially severe complications. Full article

Background/Objectives: Automation improves efficiency in laboratory workflow but may fail to detect clinically relevant abnormalities in patients with nephropathy. This study aimed to identify dipstick parameters associated with nephropathy-related sediment findings and to propose practical criteria to guide manual microscopy review based on these associations. Methods: Urine samples from in- and outpatients, primarily from the nephrology unit, were collected at a university hospital from July 2022 to September 2023. Samples were analyzed within two hours using LabUMat 2 and UriSed 3 analyzers. Manual microscopy was performed on all specimens by two experienced technicians. Sediments were classified as suggestive or not of nephropathy based on hematuria with dysmorphism, hyaline and pathological casts, lipiduria, or renal tubular epithelial cells. Results: Of 503 samples, 146 (29%) showed sediment findings indicative of nephropathy, which were significantly associated with dipstick positivity for protein and blood. Among nephropathy samples, 71.2% had protein ≥1+ or blood ≥2+. Using this combination as a criterion for manual sediment review yielded a sensitivity of 71.2%, a specificity of 73.9%, and a 3.84-fold increased relative risk of detecting nephropathy-related elements (p < 0.001). The criteria performed best among nephrology outpatients, with sensitivity of 79.5%, specificity of 63.9%, and relative risk of 3.91 (p < 0.001). Conclusions: Dipstick protein ≥1+ or blood ≥2+ helps identify patients who may benefit from manual sediment review, supporting diagnostic accuracy in nephropathy. Each institution should define its criteria based on patient profile, analytical methods, and workflow. Full article

Oxidative stress plays a crucial role in disease pathogenesis. While reactive oxygen species (ROS) directly cause cellular injury, emerging evidence suggests oxidatively modified proteins like albumin may also contribute significantly to tissue damage. Although oxidized albumin (ox-Alb) is linked to renal pathology, the direct effects and mechanisms of ox-Alb on renal cell injury remain unclear. This study was created to address these questions. In mouse models of renal injury initiated by vitamin C/copper or ischemia/reperfusion, levels of serum ox-Alb were significantly elevated. The treatment of albumin with copper/vitamin C increased Alb carbonylation and reduced the number of sulfhydryl groups, causing Alb oxidation. In cultured renal tubular epithelial NRK-52E cells, ox-Alb triggered cell death, associated with increased intracellular albumin accumulation—enhanced cellular protein carbonylation, and p38 MAPK activation. Notably, ox-Alb induced ferroptosis, evidenced by decreased GPX4 and xCT, increased ACSL4, elevated iron and lipid peroxidation, and suppression by deferoxamine and liproxstatin-1. In vivo, administration of ox-Alb exacerbated doxorubicin-induced nephropathy, as indicated by the elevated BUN, creatinine, and proteinuria, and intensified renal ferroptotic responses, including altered GPX4 and ACSL4. Our findings demonstrate that ox-Alb induces renal cell ferroptosis and promotes renal disease progression, suggesting its pivotal pathogenic role in oxidative stress-related kidney diseases. Full article

Studies on populations exposed to inorganic arsenic (iAs) have shown an association with the development of chronic kidney disease (CKD) and renal cell carcinoma (RCC). However, there are few studies addressing how acute exposure of the human kidney to iAs might lead to the long-term alterations that might lead to CKD or RCC. This laboratory’s hypothesis is that renal exposure to iAs might alter the renal cells responsible for the repair and regeneration of nephrons damaged by iAs exposure or other renal toxicants. The kidney possesses a minority epithelial cell population that co-expresses PROM1 and CD24, which are believed to be involved in renal epithelial cell repair. The purpose of this work is to understand the pathogenesis of CKD in renal cortical epithelial cells. Our model consists of acute and chronic exposure of i-As (III) to “Human Renal Tubular Precursor TERT” (HRTPT). The microarray and gene validation study demonstrated a sudden induction of microfibril associated protein 5 (MFAP5) and carcinoembryonic antigen related cell adhesion molecule 5 and 6 (CEACAM 5 and 6) in chronic i-As (III)-exposed cells. Chronically exposed cells also exhibited an induction of the pAKT/AKT pathway and SOX9 transcription factor. The targeting of MFAP5 and CEACAM 5/6 could, therefore, provide a potential therapeutic approach to CKD. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity. Full article

Acute kidney injury (AKI) causes damage to the renal epithelium, initiating a reparative process intended to restore renal function. Although effective repair can result in the complete recovery of kidney function, this process is frequently incomplete. In instances where repair is unsuccessful, the kidney experiences maladaptive alterations that may progressively result in chronic kidney disease (CKD), a phenomenon referred to as failed repair. This condition is precipitated by hypotensive, septic, or toxic insults, which initiate a series of pathophysiological processes, including microcirculatory dysfunction, the activation of inflammatory responses, and the death of tubular epithelial cells. These events collectively compromise renal function and trigger a complex repair response. This review provides a comprehensive examination of the multifactorial mechanisms underlying the initiation and progression of AKI, the regenerative pathways facilitating structural recovery in severely damaged kidneys, and the critical transition from adaptive repair to maladaptive remodeling. Central to this transition are mechanisms such as epigenetic reprogramming, G2/M cell-cycle arrest, cellular senescence, mitochondrial dysfunction, metabolism reprogramming, and cell death, which collectively drive the progression of CKD. These mechanistic insights offer a robust foundation for the development of targeted therapeutic strategies aimed at enhancing adaptive renal repair. Full article

This study investigated the protective effects of corynoxeine, a natural alkaline compound, on colistin-caused nephrotoxicity using a murine model. Forty mice were divided randomly into control, corynoxeine-only (20 mg/kg/day, intraperitoneal injection), colistin-only (20 mg/kg/day, intraperitoneal injection), and colistin (20 mg/kg/day) + corynoxeine (5 and 20 mg/kg/day) groups (8 mice in each group). All treatments were maintained for seven consecutive days. Results showed that colistin treatment at 20 mg/kg/day for seven days significantly increased serum urea nitrogen and creatinine levels and induced the loss and degeneration of renal tubular epithelial cells, which were markedly ameliorated by corynoxeine co-treatment at 5 or 20 mg/kg/day. Corynoxeine supplementation also markedly attenuated colistin-induced increases in malondialdehyde levels and decreases in reduced glutathione levels and superoxide dismutase and catalase activities in the kidneys. Furthermore, corynoxeine supplementation significantly decreased the expression of transforming growth factor β (TGF-β) and nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) proteins and nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-α mRNAs, while it significantly increased the expression of erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins in the kidneys. In conclusion, these results reveal that corynoxeine can protect against colistin-induced nephrotoxicity in mice by inhibiting oxidative stress and inflammation, which may partly be attributed to its ability on the activation of the Nrf2/HO-1 pathway and the inhibition of the TGF-β/NOX4 and NF-κB pathways. Full article

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression. Full article

The renin–angiotensin system helps regulate the endocrine system in modulating blood pressure, fluid volume, and body fluid electrolyte levels. The disruption of the renin–angiotensin system can lead to kidney disease onset and progression. However, the mechanism by which kidney angiotensinogen expression and secretion induce the onset and progression of diabetic nephropathy remains unclear. In this study, we used renal proximal tubular epithelial cells, which express high levels of angiotensinogen, to examine food components that regulate angiotensinogen secretion. The renal proximal tubular epithelial cells were first treated with catalase (antioxidant), daidzein, equol (an isoflavone), a MAP kinase inhibitor, ERK, p38, or JNK and then stimulated with hydrogen peroxide. After 24 h, we collected a culture medium to perform an enzyme-linked immunosorbent assay test for angiotensinogen and cells in order to perform real-time PCR to detect angiotensinogen. We found that angiotensinogen secretion increased as the hydrogen peroxide concentration increased. Catalase, daidzein, and equol decreased angiotensinogen expression and secretion. To investigate the cell signaling mechanism involved in these effects, we assessed the contribution of the MAP kinase cascade. Our data suggest the contribution of p38 and JNK. Our study shows that, in proximal tubular epithelial cells, hydrogen peroxide stimulates angiotensinogen secretion. Isoflavones and p38 inhibited angiotensinogen secretion. Full article

Renal fibrosis is a critical pathological feature of various chronic kidney diseases, with hypoxia being recognized as an important factor in inducing fibrosis. Yaks have long inhabited high-altitude hypoxic environments and do not exhibit fibrotic damage under chronic hypoxia. However, the underlying protective mechanisms remain unclear. This study compared the renal tissue structure and collagen volume between low-altitude cattle and high-altitude yaks, revealing that yaks possess a significantly higher number of renal tubules than cattle, though collagen volume showed no significant difference. Under hypoxic treatment, we observed that chronic hypoxia induced renal fibrosis in cattle, but did not show a significant effect in yaks, suggesting that the hypoxia adaptation mechanisms in yaks may have an anti-fibrotic effect. Further investigation demonstrated a significant upregulation of P-AMPK/AMPK, Parkin, PINK1, LC3Ⅱ/Ⅰ, and BECN1, alongside a downregulation of P-mTOR/mTOR in yak kidneys. Additionally, hypoxia-induced renal tubular epithelial cells (RTECs) showed increased expression of mitophagy-related proteins, mitochondrial membrane depolarization, and an increased number of lysosomes, indicating that hypoxia induces mitophagy. By regulating the mitophagy pathway through drugs, we found that under chronic hypoxia, activation of mitophagy upregulated E-cadherin protein expression while downregulating the expression of Vimentin, α-SMA, Collagen I, and Fibronectin. Simultaneously, there was an increase in SLC7A11, GPX4, and GSH levels, and a decrease in ROS, MDA, and Fe²⁺ accumulation. Inhibition of mitophagy produced opposite effects on protein expression and cellular markers. Further studies identified ferroptosis as a key mechanism promoting renal fibrosis. Moreover, in renal fibrosis models, mitophagy reduced the accumulation of ROS, MDA, and Fe²⁺, thereby alleviating ferroptosis-induced renal fibrosis. These findings suggest that chronic hypoxia protects yaks from hypoxia-induced renal fibrosis by activating mitophagy to inhibit the ferroptosis pathway. Full article

Chronic kidney disease (CKD) is characterized by functional and structural abnormalities, with its progression strongly influenced by oxidative stress and inflammatory responses, ultimately leading to renal fibrosis. This study aimed to investigate the effects of a Ganoderma lucidum and Robinia pseudoacacia flower extract complex (NEPROBIN) through in vitro and in vivo experiments. In vitro experiments with NRK52E renal tubular epithelial cells demonstrated that NEPROBIN significantly alleviates H₂O₂-induced oxidative stress and suppresses lipopolysaccharide (LPS)-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Additionally, NEPROBIN reduced LPS-induced NF-κB transcriptional activity and downregulated the expression of cytokines and chemokines in these cells. We further investigated the effects of NEPROBIN in vivo. Kidney damage was induced in mice using a 0.25% adenine diet (AD), and the mice were orally treated with NEPROBIN at doses of 100, 200, and 400 mg/kg/day for two weeks. NEPROBIN treatment significantly reduced AD-induced elevations in blood urea, serum creatinine, and urinary β2-microglobulin levels. Markers of oxidative stress and kidney damage were notably lower in the kidneys of NEPROBIN-treated mice. Furthermore, NEPROBIN effectively mitigated the AD-induced inflammatory response in the kidneys, with a marked reduction in cytokine and chemokine expression. This decrease in inflammation was associated with a significant reduction in tubulointerstitial fibrosis. Overall, NEPROBIN alleviated renal damage and fibrosis by directly targeting renal oxidative stress and inflammation, highlighting its potential as a therapeutic agent for CKD. Full article

Acute kidney injury (AKI) is a common critical clinical disease with high morbidity and mortality rates. Ischemia-reperfusion (IR) is the main cause of AKI, and there is no effective treatment or prevention. Therefore, it is critical to screen for effective therapeutic agents and to find therapeutic targets. DKS26 is a derivative of oleanolic acid (OA) optimized for bioavailability while retaining the anti-inflammatory, antioxidant, and anti-apoptotic properties of OA. This study aimed to investigate the therapeutic effects of DKS26 on AKI and its underlying molecular mechanisms. We established an AKI model in vivo and in vitro and observed that DKS26 had an ameliorative effect on IR or H/R-induced renal tubular epithelial cell injury and reduced oxidative stress, inflammation, and apoptosis. Meanwhile, Swiss TargetPrediction and AutoDock Vina analysis revealed that DKS26 may interact with vitamin D receptors (VDR) through hydrogen bonding, suggesting that DKS26 may exert effects through VDR. In this study, we found that DKS26 treatment enhanced the stability of the VDR protein, promoted the binding of VDR to p-NF-κB P65^Ser311, reduced the entry of p-NF-κB P65^Ser311 into the nucleus, and inhibited the transcription of downstream inflammatory genes as well as their own expression, thus exerting its protective effect. In summary, these findings suggest that DKS26 may be a promising preventive strategy and provide a theoretical and experimental basis for AKI treatment. Full article