Search Results (1,265)

Severe subacute exposure to aluminium chloride (AlCl₃) impairs renal function and induces cortical tubular injury; however, the concomitant balance between injury and repair in tubular epithelia remains incompletely defined. Accordingly, we aimed to use a high-dose regimen of AlCl₃ (100 mg·kg⁻¹·day⁻¹ for 30 days, oral gavage) as a standardised renal stressor in male Wistar rats to quantify shifts along the injury–repair balance in the renal cortex and to test whether L-carnitine (LC) pretreatment (200 mg·kg⁻¹·day⁻¹) can attenuate these shifts. Twenty rats were assigned to four groups: control, LC alone, AlCl₃ alone, and LC followed 60 min later by AlCl₃. On day 31, we assessed body-weight gain, renal functional markers, blinded cortical lesion scoring, quantitative histochemistry, and immunohistochemical profiling of cleaved caspase-3 (apoptotic signalling) and Ki-67 (proliferative engagement) within the same cortical compartment. AlCl₃ exposure produced a severe renal stress phenotype compared with controls, reducing body-weight gain from 99.8 ± 8.6 to 24.0 ± 8.3 g and increasing serum urea and creatinine from 26.40 ± 3.21 to 48.60 ± 5.81 mg/dL and from 0.606 ± 0.063 to 0.956 ± 0.147 mg/dL, respectively. Cortical injury increased from 0 (0–0) in controls to 15 (15–15) after AlCl₃ exposure. AlCl₃ also reduced strong PAS area from 97.92 ± 1.10% to 52.37 ± 14.68% and protein optical density from 0.353 ± 0.020 to 0.269 ± 0.039, while increasing collagen area fraction from 6.92 ± 1.67% to 18.40 ± 3.02% and cleaved caspase-3 from 1.0 (1.0–2.0) to 12.0 (12.0–12.0). Ki-67 labelling declined from 17.80 ± 3.35% to 6.00 ± 1.58%, indicating suppressed proliferative engagement. Compared with AlCl₃ alone, LC pretreatment showed partial protection, with higher body-weight gain (70.0 ± 15.6 g), lower serum urea and creatinine (21.40 ± 2.30 mg/dL and 0.580 ± 0.084 mg/dL), lower cortical injury burden [3 (3–4)], greater strong PAS area (89.25 ± 2.67%), higher protein optical density (0.354 ± 0.012), lower collagen area fraction (12.26 ± 1.70%), lower cleaved caspase-3 [4.0 (4.0–6.0)], and higher Ki-67 labelling (10.60 ± 2.30%). Residual cortical injury, persistent collagen elevation, and incomplete Ki-67 preservation indicate that LC pretreatment attenuated, but did not fully prevent, AlCl₃-induced renal cortical alterations. Overall, high-burden AlCl₃ exposure not only enhanced cell loss but also impaired regenerative renewal, whereas LC pretreatment partially preserved this injury–repair balance. Full article

Renal-resident macrophages (RMs) are essential regulators of kidney homeostasis and repair, yet the mechanisms governing RM niche regeneration after acute depletion remain poorly defined. To overcome these limitations, we have developed an inducible human CD59- intermedilysin (hCD59-ILY) ablation system, enabling rapid, specific, and reversible depletion of targeted macrophage populations, and subsequent replenishment of RMs, followed by longitudinal scRNA-seq analysis of kidneys at baseline and days 1, 3, and 7 post-ablation. RM ablation triggered a rapid and sustained upregulation of Cx3cl1, predominantly in proximal tubular epithelial cells (PTC1/PTC2), establishing a persistent chemotactic niche signal that coincided with macrophage repopulation. Regenerating RMs transitioned from inflammatory/stress-associated states toward metabolically active and proliferative phenotypes enriched in glycolysis, oxidative phosphorylation, MYC, and cell-cycle programs, with attenuation of canonical inflammatory pathways. Cell–cell communication analysis revealed an early burst of intercellular signaling at day 1, followed by progressive normalization, with fibronectin (Fn1), osteopontin (Spp1), chemokine (Ccl), and amyloid precursor protein (App) axes emerging as key mediators of niche restoration. Transcriptional network analysis identified a conserved regulatory module (Tfe3, Mitf, Hif1a, Myc, Gabpa, Rcor1) coordinating macrophage differentiation and regenerative programming, linking metabolic adaptation to lineage reconstitution. Sub-clustering revealed five dynamically shifting RM subsets with distinct inflammatory, remodeling, proliferative, and surveillance states, reflecting a hierarchical regeneration process. Functional validation using clodronate-mediated depletion in Secreted Phosphoprotein 1 (Spp1) (Opn)-deficient mice demonstrated impaired macrophage repopulation, establishing osteopontin as a critical regulator of RM regeneration. Together, these data define a coordinated epithelial–immune circuit in which Cx3cl1-driven chemotaxis, Spp1-dependent signaling, and a core transcriptional network orchestrate macrophage niche reconstitution and kidney repair following acute immune cell ablation. Full article

Background/Objectives: Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and delayed graft function after kidney transplantation. Oxidative stress, mitochondrial dysfunction, and tubular epithelial cell apoptosis are central events in renal IRI. Sophocarpine (SOP), a quinolizidine alkaloid derived from Sophora species, has reported antioxidant and anti-apoptotic activities, but its effects in renal IRI remain unclear. This study investigated the role and function of SOP in renal IRI. Methods: A bilateral renal IRI mouse model and a hypoxia/reoxygenation (H/R) model in HK-2 human proximal tubular epithelial cells were used. Renal function, histological injury, apoptosis, reactive oxygen species, malondialdehyde, superoxide dismutase activity, glutathione, mitochondrial morphology, mitochondrial membrane potential, and mitochondrial dynamics-related proteins were evaluated. SIRT1 dependency was examined using Sirt1 small interfering RNA in HK-2 cells and EX527-mediated SIRT1 inhibition in mice. Results: SOP pretreatment reduced serum creatinine and blood urea nitrogen levels, attenuated tubular injury and apoptosis, decreased oxidative stress, and preserved mitochondrial morphology and function after renal IRI. Similar protective effects were observed in HK-2 cells exposed to H/R. SOP increased SIRT1 and PGC-1α expression, whereas Sirt1 knockdown or pharmacological SIRT1 inhibition weakened the antioxidant and mitochondrial protective effects of SOP. Conclusions: SOP attenuates renal IRI-associated oxidative stress and mitochondrial dysfunction, at least in part through the SIRT1/PGC-1α axis. These findings support further investigation of SOP as a candidate renoprotective compound for ischemic kidney injury. Full article

Tubulointerstitial fibrosis (TIF) represents the final common pathway leading to end-stage renal disease (ESRD) in chronic kidney disease (CKD). Despite fibrosis being well established as a key pathological hallmark, the molecular mediators that drive this process remain incompletely understood. BPI fold-containing family A member 2 (BPIFA2), a secreted innate immune protein of the sPLUNC family, was upregulated in renal tubular epithelial cells across diverse CKD etiologies and strongly correlated with collagen I accumulation and TIF severity. Tubule-specific knockdown of BPIFA2 significantly alleviated renal histopathological injury and fibrosis, whereas exogenous BPIFA2 administration aggravated fibrotic progression. Mechanistically, BPIFA2 promoted epithelial–mesenchymal transition (EMT) in tubular epithelial cells and triggered macrophage-to-myofibroblast transition (MMT) associated with the TGF-β/Smad3 signaling pathway. In conclusion, our findings identify BPIFA2 as a novel profibrotic mediator in CKD. Targeting BPIFA2 or its downstream signaling may offer new therapeutic opportunities for chronic kidney disease. Full article

Background: Renal ischemia–reperfusion injury (RIRI) is a major cause of acute kidney injury (AKI) and contributes to delayed graft function and progression toward chronic kidney disease. In addition to oxidative stress and inflammation, RIRI induces profound metabolic derangements, particularly suppression of tubular fatty-acid β-oxidation (FAO), leading to energetic stress, lipid accumulation, and maladaptive repair. Peroxisome proliferator–activated receptor-α (PPARα) is a key regulator of tubular FAO, but whether Schisandrin B (Sch B) mitigates RIRI through restoration of a PPARα-associated metabolic program remains unclear. Objective: To determine whether Sch B alleviates RIRI in association with restoration of tubular FAO and attenuation of lipid accumulation and fibrotic remodeling. Methods: A unilateral murine renal I/R model and an HK-2 hypoxia/reoxygenation (H/R) model were used. Mice received Sch B (20 or 40 mg/kg/day) before I/R, and a subset was co-treated with the PPARα antagonist GW6471. Renal function, tubular injury, fibrosis, lipid accumulation, and FAO-related proteins were assessed by serum biochemistry, histopathology, Oil Red O staining, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Bulk RNA-seq and public single-cell RNA-seq datasets were integrated to characterize metabolic pathway remodeling and cell-type-associated PPARα changes. Molecular docking and molecular dynamics simulations were performed to explore the potential interaction between Sch B and PPARα. Results: Sch B significantly improved renal function, reduced tubular injury, and attenuated interstitial collagen deposition after I/R. Sch B also reduced lipid droplet accumulation, preserved mitochondrial ultrastructure, and restored the expression of FAO-related proteins, including CPT1A, CPT2, and ACADM. In vivo and in vitro, Sch B decreased α-SMA, COL1A1, and vimentin expression, indicating attenuation of EMT-associated/profibrotic remodeling. Integrated transcriptomic analyses supported marked metabolic reprogramming after I/R, with enrichment of FAO- and PPAR-related pathways and reduced PPARα expression predominantly in tubular compartments. Sch B was associated with restoration of tubular PPARα expression, while docking and molecular dynamics analyses supported a plausible Sch B–PPARα interaction in silico. GW6471 blunted the beneficial effects of Sch B on fibrosis-related and FAO-related readouts. Conclusions: Sch B alleviates RIRI and limits subsequent fibrotic remodeling in association with restoration of a PPARα-related tubular FAO program, reduced lipid accumulation, and preservation of tubular metabolic homeostasis. These findings identify metabolic reprogramming as an important component of Sch B-mediated renoprotection, although the precise mode by which Sch B regulates PPARα requires further investigation. Full article

Background and Clinical Significance: IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory, immune-mediated multisystem disorder that can mimic neoplastic, infectious, or autoimmune conditions. Among its head-and-neck manifestations, IgG4-related dacryoadenitis and sialadenitis, historically referred to as Mikulicz disease, should be distinguished from the classical Mikulicz syndrome, which describes secondary lacrimal and salivary gland enlargement due to other systemic disorders. Renal involvement, most commonly in the form of IgG4-related tubulointerstitial nephritis (IgG4-TIN), is less frequent but carries major prognostic implications because delayed diagnosis may lead to irreversible kidney damage. Case Presentation: A 49-year-old man with no relevant past medical history presented with a 2-year history of intermittent polyuria and foamy urine. Laboratory testing revealed advanced kidney dysfunction, with serum creatinine of 4.2 mg/dL, estimated glomerular filtration rate of 16 mL/min/1.73 m², and proteinuria of 2874 mg/day. Physical examination showed bilateral parotid enlargement, upper eyelid edema, lacrimal gland enlargement, and sicca symptoms, raising suspicion for IgG4-related dacryoadenitis and sialadenitis (Mikulicz disease). Further work-up demonstrated marked eosinophilia, polyclonal hypergammaglobulinemia, and significantly elevated serum IgG4 levels (3180 mg/dL), while infectious serologies and autoimmune studies were negative. Kidney biopsy revealed plasma cell-rich tubulointerstitial nephritis with lymphoplasmacytic and eosinophilic infiltrates, interstitial fibrosis, tubular atrophy, and more than 40 IgG4-positive plasma cells per high-power field, supporting the diagnosis of IgG4-related tubulointerstitial nephritis in the setting of systemic IgG4-RD. Treatment with prednisone followed by mycophenolate mofetil led to improvement in glandular manifestations and a partial reduction in proteinuria, but renal recovery remained incomplete. The patient subsequently developed a severe pulmonary infection complicated by sepsis and oligoanuric acute kidney injury superimposed on chronic kidney disease, and ultimately progressed to end-stage kidney disease requiring chronic maintenance hemodialysis. Conclusions: This case highlights that a Mikulicz disease phenotype may represent the initial manifestation of systemic IgG4-RD and should prompt evaluation for extraglandular involvement, particularly renal disease. In patients with glandular enlargement, eosinophilia, hypergammaglobulinemia, and unexplained renal dysfunction, IgG4-RD should be actively considered. Kidney biopsy remains essential for diagnostic confirmation and prognostic assessment, as delayed recognition may result in irreversible renal damage and progression to end-stage kidney disease. Full article

Acute kidney injury (AKI) caused by ischemia–reperfusion injury (IRI) involves rapid activation of innate immune responses, in which myeloid-derived immune cells critically shape injury severity. Y-box binding protein 1 (YB-1) regulates pro-inflammatory gene expression intracellularly and can be secreted to function extracellularly, yet how these two compartments jointly influence early IRI pathology remains poorly understood. To dissect the roles of intracellular myeloid versus extracellular YB-1, we subjected myeloid-specific Ybx1 knockout, Ybx1^fl/fl × LysM^cre, mice and wild-type (WT) littermates to unilateral renal IRI following administration of either a neutralizing anti-YB-1 antibody or control IgG. Kidney injury, inflammation, immune cell recruitment, neutrophil extracellular trap (NET) formation, antibody localization, and Fcγ receptor expression were assessed by qRT-PCR, histology, immunostaining, Western blotting, and flow cytometry. Myeloid-specific knockout of Ybx1 markedly reduced renal inflammation, neutrophil infiltration, NET formation, and tubular injury. This protective phenotype was lost when extracellular YB-1 was simultaneously reduced: anti-YB-1 treatment in knockout mice restored pro-inflammatory cytokine expression, increased tubular damage markers such as NGAL and KIM-1, exacerbated neutrophil recruitment and NET formation, and led to luminar accumulation of YB-1/anti-YB-1 immune complexes in tubular cells. Mechanistically, Ybx1-deficient myeloid cells exhibited significantly reduced CD16 expression, pointing to impaired Fcγ receptor-mediated phagocytosis as the cause of defective immune complex clearance. In contrast, wild-type mice efficiently cleared extracellular YB-1 complexes and showed no injury aggravation upon antibody treatment. Our findings identify myeloid YB-1 as a central regulator of early inflammatory injury in renal IRI and reveal that its protective depletion becomes pathogenic when extracellular YB-1 is simultaneously neutralized, likely due to unmasked defects in immune complex clearance. Full article

The kidney is a highly specialized organ that maintains systemic homeostasis through tightly coordinated cellular and molecular mechanisms. Renal parenchymal cells regulate metabolic waste excretion, electrolyte and acid–base balance, and blood pressure control—functions that rely on the dynamic integration of intracellular organelles. Recent advances in molecular and biochemical research have highlighted how inter-organelle communication is essential for preserving renal cell function and adaptive responses to stress. This review focuses on the molecular crosstalk among key organelles—including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and peroxisomes—primarily in tubular epithelial cells. We discuss how these interactions coordinate metabolic signaling, protein homeostasis, redox balance, and energy production and how their disruption contributes to maladaptive pathways during acute kidney injury (AKI), ultimately promoting chronic kidney disease (CKD) transition. Particular focus is placed on emerging pathways linking organelle dysfunction to inflammation, fibrosis, and metabolic reprogramming. Furthermore, we highlight recent advances in genetics and molecular therapeutics targeting organelle communication, including modulation of ER stress responses, mitochondrial biogenesis, and lysosomal function. Clinically approved agents, such as mTOR inhibitors, and experimental approaches—such as chemical chaperones and mitochondrial transplantation—demonstrate the potential to restore organelle homeostasis and mitigate renal injury. Overall, elucidating the molecular networks governing organelle crosstalk provides critical insights into kidney disease pathogenesis and identifies novel targets for therapeutic intervention in AKI-to-CKD transition. Full article

Hemolytic Uremic Syndrome (HUS) is a severe clinical manifestation primarily triggered by Shiga toxin-producing Escherichia coli (STEC). While Shiga toxins (Stx) are central to the development of systemic endothelial damage, current recombinant antibody developments have overwhelmingly focused on neutralizing the Stx2 subtype. However, numerous STEC isolates produce Stx1 either independently or alongside Stx2, revealing a critical need to diversify the antibody repertoire for comprehensive antitoxin therapies. To address this, we characterized two novel, fully human recombinant Fabs targeting Stx1 (FabB6:Stx1 and FabC8:Stx1) selected from a synthetic library via phage display. We evaluated their binding specificity and neutralizing activity in Vero and human proximal tubular epithelial (HK-2) cells, as well as in primary human glomerular endothelial cells (HGEC exposed to HUS-derived STEC supernatants. Both Fabs exhibited high specificity and nanomolar affinity for Stx1. Notably, they displayed cell-type-dependent neutralization profiles, with FabC8:Stx1 demonstrating superior and more consistent neutralization in HK-2 cells. Crucially, when evaluated alongside previously characterized anti-Stx2 antibodies (FabC11:Stx1/Stx2 and FabF8:Stx2), the Stx1-specific Fabs conferred complementary protection against clinical STEC isolates. These findings support the inclusion of Stx1-targeting recombinant antibodies into broader multi-toxin neutralization strategies, thereby expanding the therapeutic potential against STEC-associated diseases. Full article

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease with limited therapeutic options. Ferroptosis contributes to renal tubular injury in DN. This study investigates whether mesenchymal stem cells (MSCs) ameliorate DN by inhibiting ferroptosis and elucidates the underlying mechanism. In a rat model of type 2 DN, MSCs transplantation improved renal function and histopathology, while reducing mitochondrial dysfunction, iron overload, and ROS-driven ferroptosis. In vitro, MSCs reversed high glucose-induced ferroptosis hallmarks in tubular epithelial cells. Mechanistically, RNA sequencing identified the MAPK/ERK pathway as key. MSCs suppressed the p-ERK/ERK-GPX4/ACSL4 axis, preventing glutathione depletion and lipid peroxidation. Activation of ERK abolished MSCs’ protection, whereas ERK inhibition mimicked it. These findings reveal that targeting ERK-mediated ferroptosis in renal tubules offers a novel therapeutic strategy, with MSCs acting through this specific mechanism. Full article

Background and Objectives: Vitamin D signaling plays critical roles in immune regulation, bone metabolism, and cellular differentiation across multiple tissues. However, the spatial and temporal expression patterns of key vitamin D signaling components—the vitamin D receptor (VDR) and the enzyme 1α-hydroxylase (encoded by CYP27B1)—during human nephrogenesis have not been mapped at the protein level. The primary objective of this study was to characterize VDR and 1α-hydroxylase expression across critical stages of human kidney development, complementing prior transcriptomic and single-cell descriptions, and to contextualize these developmental observations against the dysregulation of vitamin D pathway genes in adult renal and urothelial malignancies. Materials and Methods: Immunofluorescence analysis was performed on FFPE kidney tissue from 12 specimens (3 per stage) at 10, 22 and 38 gestational weeks and postnatally at 1.5 years. For each specimen, at least three non-adjacent sections were stained and 6 non-overlapping cortical fields were imaged at ×40 (18 fields per stage). Fluorescence-area percentages were quantified in ImageJ 1.54g, and group differences were assessed by one-way ANOVA with Tukey’s post hoc test at both field- and specimen-level. An accompanying bioinformatic analysis evaluated the differential expression of VDR, CYP27B1, and CYP24A1 in adult renal and urothelial malignancies (TCGA cohorts: KICH, KIRC, KIRP, BLCA) using unpaired Welch’s t-test, with Benjamini–Hochberg FDR correction applied across all 16 tumor-versus-normal comparisons (12 gene-wise + 4 post hoc log₂(CYP24A1/CYP27B1) ratios). Results: VDR showed its highest mean fluorescence area at 10 weeks (3.40% (95% CI 3.24–3.56); field-level Tukey p < 0.0001 versus other stages) and its lowest at 22 weeks (0.69% (0.64–0.74)). 1α-hydroxylase was also highest at 10 weeks (5.44% (5.29–5.60); p < 0.0001) and stabilized at lower levels thereafter (3.04–4.26%). Co-expression of both proteins was observed throughout development except in 22-week glomeruli. In TCGA, all 12 significant gene-wise comparisons retained significance after BH FDR correction (q < 0.05). VDR showed cohort-specific dysregulation: reduced in KICH (q = 2 × 10⁻⁴) but increased in KIRC and KIRP (q = 2 × 10⁻⁴ for both). CYP24A1 was reduced in all three renal cohorts (q ≤ 0.029) and unchanged in BLCA. CYP27B1 showed cohort-specific direction (reduced in KIRC; increased in KICH, KIRP, and BLCA). Conclusions: This study provides an initial immunofluorescence-based spatial description of VDR and 1α-hydroxylase across human kidney development, revealing a coordinated redistribution from immature glomeruli at 10 weeks to mature tubular segments at later stages. The TCGA analysis demonstrates that vitamin D pathway dysregulation in renal carcinoma is cohort-specific and is not abolished by multiple-testing correction. Together, these results indicate that the developmentally engaged vitamin D pathway retains kidney-specific functional relevance in adult renal pathology and provide a baseline reference for future mechanistic studies. Full article

Background/Objectives: Chronic urate nephropathy (CUN), also referred to as gouty nephropathy, represents a severe renal disease primarily precipitated by long-term hyperuricemia (HUA) and gout. However, the precise molecular mechanisms underlying its pathogenesis remain poorly understood. The present study was designed to explore these mechanisms from the perspective of targeted metabolomics. Methods: The HUA mice constructed by urate oxidase (Uox) gene knockout (KO) and their corresponding wild-type controls were employed for the present study. Serum clinical biochemical parameters were determined, and renal histopathological changes were evaluated using hematoxylin-eosin (HE) staining and Masson’s trichrome staining. A targeted metabolomic strategy based on multiple reaction monitoring (MRM) was utilized to profile the renal metabolic landscape of Uox-KO mice, and potential metabolic biomarkers for CUN were identified via multivariate data analysis. Results: Clinical biochemical analysis revealed a significant elevation in serum uric acid, creatinine, and urea nitrogen levels in Uox-KO mice compared with control mice. Histopathological observations confirmed a typical CUN phenotype in Uox-KO mice, characterized by renal tubular vacuolar degeneration and dilatation, desquamation of tubular epithelial cells into the lumen, neutrophil infiltration, glomerular crowding, and renal interstitial fibrosis. Metabolomic analysis identified a total of 291 differentially regulated metabolites in Uox-KO mice relative to control animals. These perturbed metabolites were involved in multiple key biochemical pathways, including amino acid biosynthesis, ABC transporter signaling pathway, purine metabolism, aminoacyl-tRNA biosynthesis, protein digestion and absorption, glycerophospholipid metabolism, and serotonergic synaptic transmission. Notably, pathological parameters, including biochemical measurements and histological observations, were significantly correlated with key differential metabolites associated with CUN progression. Furthermore, eleven differential metabolites (pyroglutamic acid, fructose, riboflavin, dimethyl-L-arginine, glucaric acid, indoxyl sulfate, palmitoylethanolamide, trimethylamine N-oxide, 3-hydroxyanthranilic acid, spermidine, and hippuric acid) were identified as potential metabolic biomarkers for the diagnosis and prognosis of CUN. Conclusions: These findings illustrate that targeted tissue metabolomic analysis constitutes a powerful tool for deciphering the molecular mechanisms of diseases, thus offering novel insights into the pathogenesis of CUN. Full article

Background: Pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, is widely employed in oncological practice; however, its propensity to induce nephrotoxicity through immune-mediated oxidative and inflammatory mechanisms remains an insufficiently characterized clinical concern. The present study comparatively investigated the renoprotective effects of flunarizine, a voltage-dependent calcium channel antagonist, and carvacrol, a monoterpene, against pembrolizumab-induced renal injury in rats. Methods: Twenty-four male Wistar albino rats were assigned to four groups (n = 6): healthy control (HG), pembrolizumab alone (PZB), flunarizine+pembrolizumab (FLPZ), and carvacrol+pembrolizumab (CCPZ). Pembrolizumab was administered intraperitoneally at 5 mg/kg; flunarizine orally at 5 mg/kg and carvacrol intraperitoneally at 50 mg/kg, once daily for seven consecutive days. Renal oxidative status was assessed by measuring malondialdehyde (MDA) and total glutathione (tGSH) levels. Histopathological evaluation was performed using hematoxylin and eosin staining. Two double immunofluorescence panels were employed to assess 3,3′-dityrosine/Hepatitis A virus cellular receptor 1 (HAVCR1) and cyclooxygenase-1 (COX-1)/cyclooxygenase-2 (COX-2) expression, respectively. Results: Pembrolizumab caused pronounced oxidative stress and inflammatory responses in renal tissue, leading to a significant increase in renal MDA levels and a marked decrease in tGSH levels. These biochemical alterations were accompanied by severe tubular degeneration and increased expression of 3,3′-dityrosine, which is associated with oxidative damage, as well as HAVCR1, a marker of cellular injury, and COX-1 and COX-2, which reflect inflammatory activity. These findings indicate that pembrolizumab disrupts the renal redox balance and activates both oxidative and inflammatory pathways in kidney tissue. Flunarizine and carvacrol significantly reduced these pathological changes. Both agents attenuated oxidative stress markers and supported antioxidant defenses, thereby alleviating tissue damage. However, flunarizine demonstrated a more pronounced renoprotective effect across all evaluated parameters, restoring MDA and tGSH levels closer to physiological values and reducing tubular injury to a minimal level. Carvacrol showed a more limited but still statistically significant protective effect. Conclusions: Both agents confer significant renoprotection against pembrolizumab-induced oxidative injury; however, flunarizine exhibits a more robust protective profile, likely attributable to its capacity to attenuate calcium-mediated mitochondrial dysfunction and preserve cellular bioenergetic homeostasis. Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with renal fibrosis as its core pathological hallmark. A central driver of this fibrosis is epithelial–mesenchymal transition (EMT), during which renal tubular epithelial cells transform into matrix-producing myofibroblasts. Endothelial–mesenchymal transition (EndMT) has also emerged as a critical contributor, and together with EMT, accounts for the progressive accumulation of myofibroblasts and extracellular matrix. A major clinical challenge in halting DKD progression is “metabolic memory”, a phenomenon whereby renal injury persists and EMT/EndMT remain activated even after glycemic control is achieved. The molecular basis underlying this sustained activation remains incompletely understood. Emerging evidence indicates that metabolic memory is largely mediated by epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNA dysregulation. These stable epigenetic imprints maintain the persistent activation of key pro-fibrotic signaling pathways, especially TGF-β, thereby continuously driving EMT, EndMT, and excessive extracellular matrix deposition. Although targeting epigenetic regulators has shown promising anti-fibrotic effects, a systematic review that integrates how metabolic memory orchestrates both EMT and EndMT through a multi-layered epigenetic network remains lacking. This review comprehensively summarizes the epigenetic mechanisms by which metabolic memory sustains EMT and EndMT in DKD, highlights key therapeutic targets, and discusses their translational and clinical implications. Full article

Renal tubular epithelial cells (RTECs) are increasingly recognized as key players in kidney diseases. They integrate metabolic, inflammatory, and fibrotic signals. This article reviews new data suggesting that RTECs could function as central integrators within diagnostic networks, linking cellular stress responses to detectable blood and urine biomarkers. We discuss the latest advances in multi-omics, extracellular vesicles, and single-cell technologies that enable precise identification of RTEC states. Finally, we discuss the potential of RTEC-centric diagnostics and highlight current limitations in early disease recognition, stratification, and the development of personalized therapeutic interventions. Full article