Search Results (397)

Doxorubicin (DOX), a widely used chemotherapeutic, is constrained by its nephrotoxicity, characterized by endothelial injury, inflammation, and oxidative stress. Vascular endothelial growth factor (VEGF) signaling in the kidney serves a dual function. Under normal conditions, it supports the survival of glomerular endothelial cells and maintains vascular stability, but when excessively activated, it disrupts angiogenesis and contributes to kidney injury. In this context, we hypothesize that Nanocurcumin (CUR-NP), a nano-formulated curcumin derivative with enhanced bioavailability, can modulate the VEGF pathway and restore regular renal activity. Thus, this study aims to explore the potential protective effect of CUR-NP on DOX-induced renal injury in male rats. Thirty-two Wistar albino rats were used and distributed into four groups. CUR-NP (80 mg/kg dissolved in 1% CMC) was administered by oral gavage for two weeks. A single dose of DOX (15 mg/kg) (i.p.) was injected on day seven of the study. Results showed that DOX increased the circulating creatinine, urea, and urea-nitrogen levels, while pretreatment with CUR-NP markedly alleviated kidney function. In addition, CUR-NP treatment significantly normalized oxidative stress markers in renal tissues, such as NO, GSH, and SOD, and improved renal pro-inflammatory mediators, TNF-α, IL-6, and NF-κB-p65. DOX caused degeneration of glomeruli and tubules with degenerated epithelial lining and casts in their lumens. Conversely, CUR-NP maintained standard tubular and glomerular structure. Immunohistochemistry showed that DOX strongly upregulated VEGF and AhR, while CUR-NP markedly reduced their expression, countering VEGF/AhR pathway disruption and helping restore physiological signaling. Full article

Background: Cannabidiol (CBD), the major non-psychotropic cannabinoid derived from Cannabis sativa L., has demonstrated broad anticancer activity across multiple tumor types; however, its effects in renal cell carcinoma (RCC) remain largely undefined. Given the ongoing need for novel therapeutic strategies in RCC, this study provides preliminary mechanistic insights into the cytotoxic, antiproliferative, and redox-modulating properties of CBD in RCC cells and evaluates the influence of serum conditions on its activity. Methods: Human RCC cell lines (Caki-1 and 769-P) and non-tumoral proximal tubular epithelial cells (HK-2) were treated with CBD (1–100 µM) for up to 48 h under serum-free and serum-supplemented (5%) conditions. Cytotoxic and antiproliferative effects were assessed using the MTT assay, and intracellular reactive oxygen/nitrogen species (ROS/RNS) levels were quantified using the H₂DCFDA fluorescence assay. Results: CBD significantly decreased RCC cell viability and proliferation in a concentration-dependent manner and induced time-dependent ROS/RNS accumulation. Comparable sensitivity was observed in non-tumoral HK-2 renal epithelial cells, indicating limited tumor selectivity under the tested in vitro conditions. Notably, these effects were markedly attenuated in the presence of serum, consistent with CBD’s high serum–protein binding and reduced free bioavailability. Conclusions: CBD induces cytotoxic, antiproliferative, and redox-modulating effects in RCC cells in vitro; however, these responses are strongly attenuated by serum, lack tumor selectivity, and require concentrations exceeding clinically achievable plasma levels. Together, these findings delineate major translational limitations for the therapeutic use of CBD in RCC. Full article

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Despite advances in metabolic and blood pressure control, the prevalence of DKD continues to rise, creating a significant clinical and socioeconomic burden. Recent studies have revealed that non-coding RNAs, particularly microRNAs (miRNAs), play an important role in the development and progression of DKD. Distinct patterns of miRNA dysregulation have been identified in specific renal cell types, including podocytes, mesangial cells, tubular epithelial cells, endothelial cells, fibroblasts, and macrophages. These alterations drive characteristic cellular injuries such as podocyte loss, mesangial matrix expansion, tubular epithelial–mesenchymal transition, endothelial dysfunction, and interstitial fibrosis. Certain miRNAs, such as miR-21, miR-192, and miR-214, reinforce profibrotic TGF-β/Smad signaling, whereas protective groups, including the miR-29 and miR-30 families, maintain epithelial stability and restrict matrix deposition. Beyond their regulatory roles, circulating and urinary miRNAs have emerged as stable, non-invasive biomarkers that reflect renal injury and disease progression. This review summarizes recent progress in elucidating cell-specific miRNA networks in DKD and highlights their potential as diagnostic indicators and therapeutic targets for precision management of diabetic kidney disease. Full article

Objective: To explore the preventive effect and mechanism of melatonin on high-fructose-induced renal injury in mice. Methods: A total of forty male C57BL/6J mice aged six weeks were randomly assigned to four groups: control group (CON), melatonin group (MLT), fructose group (FRU), and fructose + melatonin group (FRU + MLT). The concentration of the fructose solution was 30%, and the dose of melatonin was 10 mg/kg/day by intragastric administration. The experiment lasts for 10 weeks. Results: Liquid intake and energy intake were comparable between the FRU and FRU + MLT, both of which were significantly higher than that in the CON and MLT. MLT inhibited fructose-induced increased levels in serum creatinine (Cre), serum urea nitrogen (BUN), serum uric acid (UA), serum triglyceride (TG), renal kidney injury molecule-1 (KIM-1), and renal TG. Hematoxylin and Eosin (H&E) staining and Oil Red O (ORO) staining showed that MLT alleviated renal tubular dilatation, loss of brush border, epithelial cell detachment and lipid accumulation. Transmission electron microscope (TEM) observations showed that MLT increased autophagic vacuoles among mitochondria. Western blot analysis showed that, compared with the FRU, the FRU + MLT had elevated expression of AMP-activated protein kinase (AMPK) phosphorylation, along with a significant increase in the expression of its downstream mitophagy-related proteins (including PINK1, Parkin, LC3 II, and Beclin1), whereas the expression of p62 was markedly decreased. Furthermore, the expression levels of FAO-related proteins (including PPARα and CPT1A) in the FRU + MLT were significantly upregulated. Conclusions: MLT alleviates renal injury caused by high-fructose exposure in male mice and its mechanism might be associated with the regulation of mitophagy and fatty acid oxidation. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 genes, encoding polycystin-1 (PC1) or polycystin-2 (PC2), respectively, characterized by excessive cell proliferation and fluid secretion, resulting in renal cyst formation and growth. PC1 and PC2 form a complex localized on the plasma membrane, endoplasmic reticulum, and primary cilia. PC2 is a non-selective cation channel which, in renal epithelial cells, contributes to calcium transport and signaling. It has been previously shown in renal cells that high external calcium increases whole-cell currents likely mediated by PC2. In this study, we explored the possibility that the Calcium Sensing Receptor (CaSR) is involved in the functional regulation of PC2. To test this hypothesis, human conditionally immortalized Proximal Tubular Epithelial cells, isolated from urine sediments, wt or with stably downregulated PKD1 (PC1KD) or PKD2 (PC2KD) were used. Interestingly, CaSR and PC2 co-immunoprecipitated and Proximity Ligation Assay demonstrated a direct physical interaction at endogenous protein levels. Membrane potential measurements demonstrated that selective CaSR activation, elicited by the calcimimetic R568, caused plasma membrane depolarization, consistent with the modulation of PC2-mediated cation currents, which was significantly lower in PC2KD with respect to wt and PC1KD cells. To conclude, this study provides evidence for a functional coupling of CaSR and PC2, which might be relevant for therapeutic strategies to correct dysregulations occurring in ADPKD. Full article

In the pathological process of acute kidney injury (AKI) and its transition to chronic kidney disease, the uric acid (UA) metabolic pathway plays a significant role. UA is produced as the last oxidative product in the metabolism of purine nucleotides. Prolonged organ ischemia promotes the breakdown of nucleotides into adenosine, hypoxanthine, xanthine, and UA. In this study, animal models of ischemia–reperfusion-induced AKI and renal tubular epithelial cells subjected to hypoxia–reoxygenation injury exhibited significantly reduced ATP levels, along with elevated concentrations of purine catabolites, including AMP, hypoxanthine, xanthine, and UA. Concurrently, the expression of xanthine oxidase (XO), a key enzyme in purine catabolism, was upregulated, peaking at 3 h after reoxygenation, accompanied by increased reactive oxygen species (ROS) production. Treatment with the XO inhibitor febuxostat in hypoxia–reoxygenated HK-2 cells led to a marked reduction in UA, inflammatory cytokines, and ROS levels, along with decreased apoptosis and enhanced proliferative capacity. Clinical data analysis revealed that 59.4% of AKI patients presented with hyperuricemia. UA levels demonstrated a linear correlation with the estimated glomerular filtration rate (eGFR) and the tissue necrosis marker lactate dehydrogenase (LDH). A random forest model constructed based on UA, LDH, age, diabetes, and hypertension accurately predicted the eGFR. These findings indicate that patients with I/R-induced AKI exhibit enhanced purine catabolism, and purine metabolic breakdown products are closely associated with the severity of renal injury in I/R AKI. For high-risk AKI populations or patients diagnosed with AKI with significantly elevated UA levels, febuxostat may be considered to prevent AKI onset and improve renal function. Furthermore, in AKI patients where creatinine data are unavailable or not significantly elevated despite markedly increased UA levels, a comprehensive assessment incorporating relevant indicators of glomerular filtration function is recommended. Full article

Background: Oxidative stress arises from an imbalance between excessive oxidant production and impaired antioxidant defense systems. This imbalance leads to biomolecular damage, contributing to aging and age-related diseases such as chronic kidney disease (CKD). Oxidative stress is a well-established risk factor for CKD and has been reported to accelerate disease progression. Hesperidin, a flavanone glycoside abundant in citrus fruits, exhibits antioxidant, anti-hypertensive, and anti-inflammatory properties and has been suggested to attenuate CKD progression. However, its potential role in reversing oxidative damage in kidney cells remains unclear. Methods: This study aimed to investigate whether hesperidin can reverse oxidative damage in human kidney proximal tubular epithelial (HK-2) cells. Oxidative stress was induced by exposing HK-2 cells to 500 μM hydrogen peroxide (H₂O₂) for 6 h, followed by treatment with 100 μM hesperidin for 24 h. Results: Our results showed that hesperidin significantly ameliorated H₂O₂-induced cytotoxicity. In the hesperidin post-treatment group (H₂O₂ + hesperidin), the expression of the antioxidant gene manganese superoxide dismutase (MnSOD) and the longevity-associated gene sirtuin 1 (SIRT1) was upregulated, while the expression of the senescence-associated gene β-galactosidase was downregulated compared to the H₂O₂-only treatment. Conclusions: These findings suggest that hesperidin promotes recovery from oxidative injury in kidney cells by enhancing antioxidant and longevity pathways and reducing cellular senescence. This may contribute to improved renal health and potentially slow CKD progression in patients suffering from oxidative stress-related kidney damage. Full article

Diabetic kidney disease (DKD) is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of morbidity and mortality. Both metabolic and inflammatory pathways have emerged as potential sources of biomarkers that may improve DKD detection and treatment. This study investigated the relationship between gut-derived metabolites, such as acylcarnitines (ACs), uremic toxins (UTs), polyol pathway intermediates (PIs), and amino acid derivatives (AADs), and renal inflammation markers, detected in serum and urine. It included 20 healthy controls and 90 patients with T2DM, divided into normoalbuminuria, microalbuminuria, and macroalbuminuria. Serum and urine metabolites were analyzed using untargeted and targeted metabolomic assessments, whereas inflammatory markers were quantified using the ELISA technique. Statistical analysis consisted of descriptive statistics followed by univariable and multivariable linear regression analyses. Our findings revealed that serum AADs contribute to renal fibrosis progression, whereas urinary AADs indicate impaired tubular reabsorption in inflammatory conditions. Additionally, UTs and PIs are linked to inflammatory processes mediated by TNF-α but not by early renal fibrosis, whereas serum ACs appear to modulate immune responses, exerting pro-inflammatory and cytotoxic effects on tubular epithelial cells in early DKD. Thus, the metabolic and inflammatory pathways are tightly interconnected and synergistically contribute to the pathogenesis of early DKD. Full article

Type 2 diabetes mellitus (T2DM) is characterized by an uncontrolled increase in blood glucose levels and insulin resistance in cells of various tissues. Vascular complications in T2DM have an inflammatory nature. Drugs with different mechanisms of action have been developed and used to treat T2DM, initially aimed at controlling blood glucose levels. Among them, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) were developed as specific inhibitors of glucose reabsorption in the kidneys, but along with lowering blood glucose levels, they demonstrated multiple (including non-glycemic) positive effects in the treatment of T2DM related to their beneficial effects on the immune system. SGLT2 inhibitors can reduce the risk of diabetic cardiomyopathy (DCM) and chronic kidney disease (CKD) development in patients with and without diabetes. SGLT2-is improve cardio-renal complications through a number of signaling pathways, including those dependent on the involvement of non-coding RNAs (ncRNAs) and their targets. The best-studied classes of ncRNAs are microRNAs, which are short (less than 200 bases) RNAs (miRNAs), long non-coding RNAs (lncRNAs) (more than 200 bases), and circular RNAs (circRNAs). The regulatory effect of ncRNAs has broad physiological significance, and changes in the ncRNAs’ expression are associated with the pathogenesis of different diseases, including T2DM. RNA-seq allows the construction of networks of interactions of lncRNA/circRNA-miRNA-mRNA called competitive endogenous RNA (ceRNA) networks, to identify clinically significant molecular markers, to improve the mechanistic understanding of pathogenesis, and to contribute to the development of new diagnostics and therapies. Our review summarizes the role of non-coding RNA in the action of SGLT2 inhibitors in cardio-renal complications in T2DM. We focus on methods of detection, genetics, and the effects of non-coding RNA. Specific attention is given to the role of non-coding RNAs in the inflammatory reactions of innate immune cells in relation to the SGLT2 inhibitors. Full article

Excessive accumulation of lipid droplets (LDs), their dynamics, and lipotoxicity are critical factors in the progression of metabolic disorders, including diabetic nephropathy. This study investigates the effects of yomogi tea (Mugwort tea), specifically its leaf infusion (YL) and powdered infusion (YP), on lipid metabolism in human kidney proximal tubular epithelial HK-2 cells under lipotoxic conditions induced by palmitic acid (PA). Both YL and YP significantly reduced intracellular triglyceride (TG) and free fatty acid (FFA) levels, with YP showing a trend toward greater efficacy. Mechanistic analysis revealed that yomogi tea regulates lipid metabolism by significantly downregulating mRNA expression of FAS and upregulating that of the lipolytic ATGL, while SCD-1 mRNA expression remained largely unchanged. Furthermore, yomogi tea reduced LD size and neutral lipid content, potentially enhancing lipid hydrolysis efficiency and mitigating lipotoxic effects. These findings highlight the potential of yomogi tea as a natural agent for regulating lipid metabolism and reducing lipotoxicity, offering promise for managing lipid metabolism-related disorders. Full article

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease worldwide, with proximal tubular epithelial cells (PTECs) playing a central role in its pathogenesis. Under hyperglycemic conditions, PTECs drive a pathological triad of inflammation, apoptosis, and fibrosis. Recent advances reveal that these processes interact synergistically to form a self-perpetuating vicious cycle, rather than operating in isolation. This review systematically elucidates the molecular mechanisms underlying this crosstalk in PTECs. Hyperglycemia induces reactive oxygen species (ROS) overproduction, advanced glycation end products (AGEs) accumulation, and endoplasmic reticulum stress (ERS), which collectively activate key inflammatory pathways (NF-κB, NLRP3, cGAS-STING). The resulting inflammatory milieu triggers apoptosis via death receptor and mitochondrial pathways, while apoptotic cells release damage-associated molecular patterns (DAMPs) that further amplify inflammation. Concurrently, fibrogenic signaling (TGF-β1/Smad, Hippo-YAP/TAZ) promotes epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Crucially, the resulting fibrotic microenvironment reciprocally exacerbates inflammation and apoptosis through mechanical stress and hypoxia. Quantitative data from preclinical and clinical studies are integrated to underscore the magnitude of these effects. Current therapeutic strategies are evolving toward multi-target interventions against this pathological network. We contrast the paradigm of monotargeted agents (e.g., Finerenone, SGLT2 inhibitors), which offer high specificity, with that of multi-targeted natural product-based formulations (e.g., Huangkui capsule, Astragaloside IV), which provide synergistic multi-pathway modulation. Emerging approaches (metabolic reprogramming, epigenetic regulation, mechanobiological signaling) hold promise for reversing fibrosis. Future directions include leveraging single-cell technologies to decipher PTEC heterogeneity and developing kidney-targeted drug delivery systems. We conclude that disrupting the inflammation–apoptosis–fibrosis vicious cycle in PTECs is central to developing next-generation therapies for DN. Full article

Background: G2/M cell cycle arrest of proximal tubular epithelial cells following acute kidney injury results in maladaptive repair and promotes chronic kidney disease. We investigated whether erythropoiesis-stimulating agents (ESA) regulate G2/M arrest and mitigate kidney fibrosis. Methods: Human kidney 2 (HK-2) cells were stimulated with TGF-β or paclitaxel, treated with darbepoetin alfa (DARB) at 0.5 ug/mL or 5 ug/mL, and cell cycles were analyzed using flow cytometry. In vivo experiments involved intraperitoneal administration of DARB (0.5 or 5 ug/kg) to the unilateral ureteral obstruction (UUO) mouse model on post-operative days three and seven. Kidney fibrosis and cell cycle regulatory proteins were analyzed using immunohistochemistry, RT-PCR, and immunoblotting. The effect of DARB on kidney fibrosis was compared with that of a p53 inhibitor. Results: In HK-2 cells treated with TGF-β or paclitaxel, G2/M cell cycle regulatory proteins were upregulated; however, this effect was reversed by DARB treatment. Immunostaining for p53 and Ki-67 indicated that the proliferative and fibrotic activities observed in TGF-β-treated HK-2 cells were mitigated by DARB treatment. Histological analysis of UUO mice using F4/80 staining and TUNEL assay showed that DARB treatment reduced inflammatory cell infiltration and apoptotic cell accumulation. Additionally, fibrotic changes assessed by Masson’s trichrome, Sirius red, and PAS staining confirmed the antifibrotic effects of DARB treatment in UUO mice, independent of changes in hemoglobin levels, suggesting a mechanism distinct from its hematopoietic effects. DARB reduced fibrosis-related markers by suppressing G2/M cell cycle regulatory markers and inhibited the JNK and p38-MAPK signaling pathways, which play key roles in kidney fibrosis in TGF-β-treated HK-2 cells and UUO mice. Finally, DARB treatment demonstrated an anti-fibrotic effect in HK-2 cells stimulated with TGF-β or paclitaxel, comparable to that of a p53 inhibitor. Conclusions: DARB treatment decreased G2/M cell phase arrest and attenuated kidney fibrosis, suggesting a new renoprotective mechanism for ESA. Full article

Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI), with limited targeted treatments for rhabdomyolysis-induced AKI (RIAKI) adding to the challenge. Emerging evidence implicates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) in the pathological processes of various kidney diseases, but its role in RIAKI remains unclear. We applied renal tubular epithelial cell (RTEC)-specific NOX4 knockout and the NOX4 inhibitor GKT137831 to treat RIAKI in vivo and in vitro. We found that genetic and pharmacological inhibition of NOX4 protected against glycerol-induced renal dysfunction, mitigated inflammatory responses and attenuated apoptotic rates. Additionally, NOX4 blockade suppressed the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), and enhanced the activities of antioxidant enzymes. Furthermore, NOX4 inhibition reduced the expression of endoplasmic reticulum stress (ERS)-associated proteins at both the RNA and protein levels. Collectively, these findings demonstrate that genetic and pharmacological suppression of NOX4 protects against RIAKI by reducing ROS generation, boosting antioxidant defense and inhibiting ERS activation. NOX4 inhibition may offer a potential approach for developing new treatment options for RIAKI. Full article

Background and Clinical Significance: Mucinous tubular and spindle cell carcinoma (MTSCC) is an uncommon subtype of renal cell carcinoma, representing 1–4% of epithelial renal tumors. It usually shows a low-grade morphology and indolent behavior, although sarcomatoid variants with an aggressive course have been described. Because of its overlap with papillary renal cell carcinoma (papRCC), sarcomatoid RCC, mesenchymal tumors, and oncocytic neoplasms, diagnosis requires the integration of imaging, histopathology, and immunohistochemistry. Case Presentation: We report a 71-year-old female who presented with a three-month history of right-sided lumbar pain and intermittent hematuria. Her laboratory tests were unremarkable. Contrast-enhanced CT revealed a well-circumscribed nodular lesion in the mid-portion of the right kidney, measuring 50 × 47 × 52 mm. The patient underwent right nephrectomy. Macroscopic findings revealed an encapsulated, yellowish-gray nodule (5.2 × 5 × 4 cm) without renal pelvis invasion. Microscopically, the tumor consisted of cuboidal- to spindle-shaped cells arranged in cords and tubular structures within a mucinous stroma, with focal necrosis and foamy macrophages. Immunohistochemistry showed positivity for CK19, CK7, EMA, PAX8, and AMACR, with a Ki-67 index <10%, while CD117, RCC, CD10, and chromogranin were negative. Together, the low Ki-67 proliferation index, absence of invasion, and low-grade histological architecture confirmed MTSCC of low malignant potential. At a five-year follow-up, the patient remained disease-free. Conclusions: MTSCC is a rare renal neoplasm that can be diagnosed by integrating clinico-radiological, histopathological, and immunophenotypic features. Molecular profiling may further distinguish MTSCC from papRCC and identify aggressive variants. Surgical excision remains the cornerstone of management, supported by vigilant long-term follow-up. Full article

Advanced glycation end-products (AGEs) are associated with the dysfunction of proximal tubular epithelial (PTE) cells in lifestyle diseases. Urinary stones induce cytotoxicity in PTE cells, and various medicines have been developed to mitigate or prevent their generation/accumulation. The leaves of Quercus salicina Blume/Q. stenophylla Makino—used in Japanese folk medicine—contain quercetin, hesperidin, and p-hydroxycinnamic (p-coumaric) acid, which can suppress the cytotoxicity of intra-/extracellular AGEs. This review investigated the effects of quercetin, hesperidin, and p-coumaric acid on PTE cells in terms of their metabolism following oral administration and the associated organs and bacteria. Current evidence indicates that, in PTE cells, non-metabolized quercetin and p-coumaric acid may suppress intra-/extracellular AGE-induced cytotoxicity, whereas the metabolites of quercetin and hesperidin may inhibit the generation of AGEs. However, little is known of the effects of p-coumaric acid metabolites. Quercetin, hesperidin, and p-coumaric acid may collectively suppress the cytotoxicity of intra-/extracellular AGEs in PTE cells. This review on the current paradigm of Q. salicina/Q. stenophylla extract provides a useful baseline for the design of further preclinical and clinical investigations. Full article