Search Results (356)

Many metals in the environment are nephrotoxic. To better understand both similar and dissimilar responses to different metals, we compared RNA sequencing data from primary human proximal tubule epithelial kidney cells treated with arsenic, cadmium, vanadium, or uranium for 6 or 24 h. At 24 h post-treatment, arsenic- or cadmium-treated cells shared processes related to metal stress response and detoxification. Distinct characteristics of arsenic exposure included terms associated with membrane transport, immune/inflammatory signaling, and renal/urogenital development. This was in contrast to cadmium, where proteostasis and protein quality control were the dominant themes. Vanadium and uranium had limited overlaps with either arsenic or cadmium or one another. Response to vanadium revealed solute transport and stimulus detection as well as cell cycle/mitotic regulation and chromosome segregation. Uranium exposure was associated with RNA processing/splicing, proteostasis/ER stress and apoptotic signals, but there were fewer DEGs to define GO terms and themes. The results demonstrate that arsenic and cadmium initiate robust and partially overlapping transcriptional responses as early as 6 h, reflecting shared mechanisms of metal toxicity alongside individual metal-specific signatures. In contrast, uranium and vanadium elicit minimal early (6 h) transcriptional responses but develop more robust signatures by 24 h. These findings demonstrate that environmentally relevant metals act through both shared mechanistic pathways and distinct, metal-specific mechanisms. Understanding their individual and overlapping transcriptional mechanisms is critical for interpreting health risks associated with human exposure. Full article

Cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR) induces systemic ischemia and frequently results in acute kidney injury (AKI). The ketone body β-hydroxybutyrate (BHB) maintains mitochondrial and peroxisomal homeostasis through activation of the C/EBPβ–Pck1 axis, whereas Pck1 preserves mitoribosome integrity and mtDNA-encoded oxidative phosphorylation (OXPHOS) translation. However, it remains unclear whether this pathway is disrupted during CA/CPR-induced AKI and whether empagliflozin can restore its activity. Male C57BL/6J mice and proximal tubule-specific Pck1 conditional knockout (CKO) mice were subjected to short-duration or standard CA/CPR protocols. Empagliflozin was administered orally for 7 days before CA/CPR induction. Circulating BHB levels, renal expression of C/EBPβ and Pck1, and markers of mitochondrial, peroxisomal, and mitoribosomal abundance and function were evaluated using established methods. CA/CPR markedly reduced circulating BHB levels and suppressed the C/EBPβ–Pck1 signaling axis. These changes were accompanied by depletion of peroxisomal markers, mitochondrial regulators, and mitoribosomal components as well as increased tubular apoptosis and albuminuria. Pck1 CKO mice exhibited severe organelle dysfunction and aggravated renal injury. In contrast, empagliflozin restored BHB levels, preserved C/EBPβ and Pck1 expression, and maintained mitochondrial, peroxisomal, and mitoribosomal integrity, thereby attenuating tubular injury and albuminuria. Notably, empagliflozin treatment increased BHB, C/EBPβ, and Pck1 levels in noninjured mice without inducing organelle expansion, suggesting that Pck1 activation alone is insufficient to promote mitoribosome biogenesis under basal conditions. Collectively, these findings demonstrate that empagliflozin protects against CA/CPR-induced AKI and identify Pck1 as a key metabolic regulator linking ketone signaling to organelle resilience. Full article

Hyperuricemia (HUA) is a common immunometabolic disorder associated with gout, renal dysfunction, and systemic inflammation, yet the molecular targets through which non-starch polysaccharides (NSPs) may modulate HUA-related inflammation remain unclear. Here, we applied an integrative bioinformatics and computational workflow combining public transcriptomic datasets, curated NSP-related targets, protein–protein interaction analysis, enrichment analysis, single-cell RNA sequencing, and Mendelian randomization. We further included GutMGene-based orthogonal support analysis, guided docking, structural dynamics analysis, exploratory ADMET profiling, and in silico TLR4 knockout to extend target prioritization. This approach prioritized a TLR4-centered inflammatory module, with TLR4, MSR1, TIRAP, and CXCL8 emerging as candidate genes. Enrichment analyses linked these genes to innate immune and NF-$\kappa$B-related pathways, whereas single-cell analyses localized the prioritized signals mainly to myeloid compartments during gout flares. Mendelian randomization suggested positive associations between genetically predicted expression of TLR4-axis genes and serum uric acid levels. Under electrostatic-guided docking conditions, fucoidan and alginate yielded plausible interaction models with TLR4, and normal mode and RMSF analyses suggested altered flexibility in the MD-2 region. In silico Tlr4 knockout further perturbed urate-handling programs in renal proximal tubule-enriched cells. Together, these findings do not establish TLR4 as a newly discovered hyperuricemia gene or confirm direct receptor antagonism by NSPs, but they provide an NSP-oriented integrative framework that prioritizes the TLR4 axis, highlights myeloid-cell relevance, and nominates fucoidan and alginate for experimental follow-up. Full article

Renal tubular disorders are often overlooked causes of acquired or inherited bone hypomineralization and fragility fractures in adults. The proximal tubule reabsorbs glucose, phosphate, low-molecular-weight proteins, amino acids, bicarbonate, and much of the sodium, potassium, chloride, and calcium. The distal nephron—the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the collecting duct—regulates urine concentration and dilution, maintains acid-base balance via urinary proton secretion, and controls electrolytes, including sodium, potassium, magnesium, and calcium. Tubular defects may cause hyperphosphaturia (high urinary phosphate), hypercalciuria (high urinary calcium), or chronic metabolic acidosis (renal tubular acidosis, RTA). These changes weaken bone mineralization, disrupt bone turnover, and raise the risk of muscle weakness and fractures. This review summarizes acquired and genetic tubulopathies linked to hyperphosphaturia, hypercalciuria, and RTA and outlines a practical diagnostic approach for outpatients with bone fragility and suspected renal tubulopathy. 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: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [¹³C₂]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target. Full article

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

Renal cancer remains a major global health burden, and current targeted and immunotherapeutic strategies are frequently limited by toxicity, therapeutic resistance, and suboptimal response rates. Natural bioactive compounds such as epigallocatechin gallate (EGCG) and cafestol exhibit anticancer activity; however, their therapeutic utility is constrained by limited potency and dose-dependent adverse effects. In this study, the antiproliferative and synergistic effects of cafestol and a hyaluronic acid (HA)–EGCG conjugate were investigated in renal cancer cells. HA conjugation significantly enhanced the antiproliferative efficacy of EGCG in both ACHN and A498 human renal cancer cells, whereas unmodified HA exhibited no intrinsic anticancer activity. Importantly, the HA–EGCG conjugate enabled a pronounced synergistic interaction with cafestol, particularly in ACHN cells, as confirmed by combination index analysis, while free EGCG and cafestol failed to achieve synergistic inhibition. In addition, the HA–EGCG conjugate and its combination with cafestol exhibited favorable selectivity toward renal cancer cells compared with normal renal proximal tubule epithelial cells (RPTECs). This combination robustly enhanced apoptosis and was associated with significant downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL at the transcriptional level, together with suppression of the epithelial–mesenchymal transition-associated transcription factor SNAIL at both transcriptional and protein levels. Notably, the enhanced antiproliferative effects were achieved at reduced concentrations, highlighting the potential to mitigate dose-related toxicity. Collectively, these findings support HA-based conjugation as an effective strategy to potentiate the anticancer activity of natural bioactive compounds and to enable synergistic, multi-targeted therapeutic effects against renal cancer. Full article

Background/Objectives: Type 2 diabetes is a group of metabolic disorders whose pathophysiological outcome is sustained hyperglycemia. Several medications are available for the treatment. SGLT2 simultaneously inhibits glucose and sodium reabsorption in the renal proximal tubule, resulting in urinary glucose excretion. This study assessed the pharmacokinetic profiles of two empagliflozin 25 mg drug products under fasting conditions in healthy Mexican subjects to establish bioequivalence. Methods: This was a randomized, open-label, two-way crossover, single-dose, prospective study with a 7-day washout period. Eligible subjects were healthy adult Mexican volunteers. The drugs were dosed orally, according to the randomization, after 10 h of fasting and 4 h before breakfast, with 250 mL of 10% glucose solution at room temperature. Serial blood samples were collected before and after dosing. Empagliflozin concentrations were analyzed using high-performance liquid chromatography–tandem mass spectrometry. Results: A total of 32 subjects were enrolled, and 30 completed the study. Pharmacokinetic parameters C_max, t_max, AUC_0–t, AUC _0–∞, and t_½ of empagliflozin for test and reference formulation, expressed as mean ± SD, were 578.28 ± 125.60 ng/mL, 2.72 ± 0.85 h, 4370.88 ± 769.50 ngh/mL, 4423.93 ± 776.02 ngh/mL, 7.62 ± 0.83 h, and 593.99 ± 156.78 ng/mL, 2.86 ± 1.00 h, 4313.24 ± 885.02 ngh/mL, 4368.04 ± 887.75 ngh/mL, and 7.61 ± 0.68 h, respectively. The 90% CI for C_max, AUC_0–t, and AUC _0–∞ were 98.30 [92.72–104.22], 101.72 [98.77–104.77], and 101.64 [98.73–104.63], respectively. Serious adverse events were not observed. Conclusions: Our study demonstrated bioequivalence between the empagliflozin formulations tested in healthy subjects under fasting conditions. Full article

Pesticide exposure is a plausible but incompletely characterized contributor to kidney injury. This review integrates current clinical, epidemiologic, experimental, and mechanistic evidence on pesticide-related nephrotoxicity, focusing on glyphosate-based herbicides, paraquat, organophosphate insecticides, and atrazine. A structured search of PubMed and Web of Science identified English-language studies published between January 2015 and February 2026. Of 635 records screened, 61 human studies were retained for full-text evaluation, and relevant animal, in vitro, and regulatory sources were additionally reviewed for mechanistic interpretation. Across pesticide classes, the proximal tubule emerged as the most consistent renal target, although downstream pathways differed, including oxidative stress, mitochondrial dysfunction, transporter disruption, endoplasmic reticulum stress, inflammation, apoptosis, ferroptotic signaling, and fibrotic remodeling. Human evidence was strongest for acute kidney injury following severe poisoning, whereas associations between chronic occupational or environmental exposure and chronic kidney disease or end-stage renal disease were more limited and heterogeneous. Biomarkers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), β₂-microglobulin, cystatin C, interleukin-18 (IL-18), cytochrome c, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) often detected early tubular stress before abnormalities appeared in conventional renal indices. Overall, pesticide nephrotoxicity is best conceptualized as a spectrum of mechanism-specific tubular injury signatures, supporting a shift toward biomarker-informed early detection, improved hazard identification, and more mechanistically grounded risk assessment. Full article

Hereditary renal tubulopathies are rare monogenic disorders caused by defects in tubular transport mechanisms that impair the handling of electrolytes, water, and acid–base balance along the nephron. While each tubulopathy is individually uncommon, their collective burden is clinically relevant, as these disorders can severely affect quality of life and predispose to nephrolithiasis, dehydration episodes, and progression to chronic kidney disease. Advances in molecular genetics have identified more than 70 genes involved in renal tubular physiology; however, a substantial proportion of these cases remain genetically unresolved, and marked phenotypic heterogeneity complicates diagnosis and management. This narrative review provides an integrated overview of the main transport systems operating in the different tubular segments of the nephron—proximal tubule, thick ascending limb of the loop of Henle, distal convoluted tubule and collecting duct—summarizing the tubulopathies associated with each segment and discussing in greater detail representative inherited disorders that illustrate the clinical consequences of their dysfunction. We highlight current diagnostic challenges and limitations of existing therapeutic strategies and discuss novel diagnostic approaches as well as emerging treatment options. Improved genetic diagnosis, validation of candidate biomarkers, and the development of novel therapeutic strategies will be essential to advance precision medicine and improve outcomes for patients with inherited renal tubulopathies. Full article

Sodium glucose-1 cotransporter (SGLT1) is a low-capacity, high-affinity glucose transporter expressed in the proximal renal tubule. It is also expressed in different human tissues and, primarily, in the brush border of the small intestine. At this level, SGLT1 inhibition results in an increase in glucose supply to the distal intestine with a reduction in intestinal pH and a consequent alteration of the intestinal microbiota. Specifically, SGLT1 inhibitors (SGLT1is) lead to an intensification of the production of short-chain fatty acids (SCFAs) and an enhancement of the incretin pathway. Potential mechanisms by which SGLT1is could reduce the occurrence of stroke and myocardial infarction may therefore involve the anti-inflammatory, anti-fibrotic and anti-atherosclerotic effects associated with an increased production of endogenous glucagon-like peptide-1 (GLP-1). Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. The Shen-Kang Recipe (SKR) is a traditional Chinese medicine formula used clinically to slow DKD progression, but its bioactive constituents and molecular targets remain unclear. Solute carrier family 15 member 2 (SLC15A2/PEPT2), a high-affinity peptide transporter expressed in renal proximal tubules, has been implicated in kidney pathophysiology, yet its potential role in mediating the therapeutic effects of the SKR has not been explored. Here, we evaluated the effects of the SKR in db/db mice and found that SKR treatment significantly improved renal function, attenuated glomerulosclerosis, and reduced interstitial collagen deposition. Wide-target metabolomics and quantitative proteomics revealed that the SKR broadly reversed DKD-associated metabolic and proteomic disturbances, particularly in pathways related to energy and amino acid metabolism. Proteomic analysis identified SLC15A2 as a key proximal tubule protein downregulated in DKD and selectively restored by the SKR. UPLC-Q-TOF/MS-based serum pharmacochemistry and network pharmacology highlighted quercetin as a principal bioactive component of the SKR. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) confirmed direct, high-affinity binding between quercetin and SLC15A2 (KD = 7.5 µM). In TGF-β1-stimulated HK-2 cells, quercetin suppressed epithelial-mesenchymal transition (EMT), as evidenced by restored E-cadherin and reduced N-cadherin, vimentin, and α-SMA expression; this effect was abrogated by siRNA-mediated SLC15A2 knockdown, demonstrating the functional necessity of this axis. Collectively, these findings identify a quercetin-SLC15A2 axis through which the SKR inhibits EMT and alleviates renal fibrosis in DKD, providing a mechanistic basis for its clinical application and nominating SLC15A2 as a potential therapeutic target. Full article

The common carp (Cyprinus carpio) kidney uniquely integrates excretory nephrons, renal hematopoietic tissue, and hormonally active thyroid follicles, positioning it as a candidate “multipurpose biomarker organ” for pollutants like perfluorooctanoic acid (PFOA), a prototype long-chain PFAS and persistent organic pollutant exhibiting nephrotoxic, immunotoxic, and thyroid-disrupting effects. Building on prior histological, ultrastructural, and morphometric analyses from carp exposed to waterborne PFOA (0, 200 ng L⁻¹, 2 mg L⁻¹ for 56 days), a hierarchical multipurpose index comprising nephrotoxic, immunotoxic, and thyrotoxic subindices was developed from z-scored light-, electron-microscopy, and morphometric features, enabling cross-scale integration; proximal tubule vesiculations and effete rodlet cells (RCs) were newly quantified from archival electron micrographs. The subindices captured PFOA-induced glomerular hyperfiltration with proximal protein reabsorption and collecting duct RCs recruitment (nephrotoxic); hematopoietic tissue RCs recruitment, clustering, and exocytosis (immunotoxic); and increased thyroid follicle abundance/vesiculation, cross-sectional area, and perimeter (thyrotoxic). Quantification of previously only qualitatively assessed features provided statistical validation, while radar plot integration rendered results more intuitively evident—particularly highlighting the non-monotonic thyroid response—condensing organ-level complexity into a coherent framework supporting carp kidney as a translational One Health model for multi-endpoint waterborne pollutant assessment. Full article

Chronic kidney disease (CKD) involves uremic toxin-driven tubular injury and systemic vascular dysfunction, in which mitochondrial impairment and apoptotic cell loss contribute to progressive tissue deterioration. Accordingly, a targeted EV platform is required to enable efficient miRNA delivery to the toxin-stressed tubular–endothelial compartment. Based on our previous study showing that melatonin restores miR-4516 levels under CKD-related stress, we directly loaded miR-4516 into engineered extracellular vesicles (EVs) to evaluate its effects on mitochondrial function and cell survival. Here, we engineered EVs with a G3-C12/RGD surface modification and established a miR-4516 loading strategy to enhance delivery to kidney proximal tubule cells and vascular endothelial cells. miR-4516 loading increased EV-associated miR-4516 levels without major changes in particle size distribution, and EV identity was supported by CD9 and CD81 expression. Confocal microscopy and flow cytometry demonstrated increased cellular uptake of miR-4516-loaded G3-C12/RGD-EVs compared with control EVs in TH1 proximal tubule cells and HUVECs. Under indoxyl sulfate stress, engineered EV treatment restored intracellular miR-4516 and improved mitochondrial function, as indicated by recovery of respiratory Complex I and Complex IV activities and improved Seahorse bioenergetic parameters (OCR/ECAR, basal and maximal respiration, ATP-linked respiration, and spare respiratory capacity). Annexin V staining further indicated reduced toxin-induced apoptosis. In an adenine diet-induced CKD mouse model, intravenous administration of miR-4516-loaded G3-C12/RGD-EVs improved urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine. These findings indicate that miR-4516-loaded, targeting-engineered EVs may mitigate uremic toxin-associated mitochondrial dysfunction and renal impairment in CKD. Full article