Search Results (331)

Acute kidney injury (AKI) is a critical clinical syndrome with limited effective therapies, in which renal tubular epithelial cell (RTEC) pyroptosis mediated by the NLRP3 inflammasome represents an important pathological contributor. Stress granules (SGs), dynamic membrane-less condensates, enable cells to adapt to various stress conditions, yet their role and regulatory mechanism in AKI remain unclear. Here, we identify SG persistence as a protective mechanism against AKI and show that poly(ADP-ribosyl)ation (PARylation)-mediated regulation of SG dynamics alleviates pyroptosis during renal injury. We found that SGs were prominently formed in RTECs from AKI patients, cisplatin-induced AKI mice, and cisplatin-stimulated HK-2 cells. Poly(ADP-ribose) glycohydrolase (PARG), the key enzyme for reversing PARylation, was significantly upregulated in injured renal tissues and cells. Genetic or pharmacological inhibition of PARG delayed SG disassembly, enhanced SG persistence, and mitigated renal injury. Mechanistically, persistent SGs regulated DDX3X availability and reduced DDX3X-NLRP3 inflammasome activation, thereby attenuating RTEC pyroptosis. These findings uncover a novel mechanism of SG-mediated renoprotection and highlight SG dynamics as a potential therapeutic target in AKI. Full article

Background: Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined. Objectives: This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved. Materials and Methods: An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA; n = 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms. Results: CA reduced serum uric acid (p ≤ 0.001 vs. model), creatinine (p ≤ 0.01 vs. model), and blood urea nitrogen (p ≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (all p ≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation. Conclusions: These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury. Full article

Chlorfenapyr (CFP) is a widely used pesticide associated with nephrotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. This study investigated the protective effects of limonene (LM) and its nano-liposomal formulation (LM-LNPs) against CFP-induced renal injury in rats. Animals were divided into six groups—control, LM, LM-LNPs, CFP, CFP + LM, and CFP + LM-LNPs—and treated orally for 30 days. CFP exposure resulted in marked renal dysfunction, histopathological and ultrastructural damage, suppression of the NRF2/HO-1/NQO1 antioxidant pathway, depletion of endogenous antioxidants excessive generation of reactive oxygen and nitrogen species, lipid peroxidation products, and DNA damage. These changes were accompanied by activation of NF-κB/COX-2-mediated inflammation, mitochondrial respiratory impairment, disrupted energy metabolism, and induction of apoptosis. Co-treatment with LM significantly ameliorated these alterations, whereas LM-LNPs produced greater improvements in renal function, tissue architecture, redox homeostasis, mitochondrial function, and inflammatory and apoptotic signaling. Immunohistochemical analyses further confirmed enhanced NRF2 expression and reduced NF-κB immunoreactivity in LM-LNP-treated kidneys. Overall, nano-liposomal delivery enhanced the renoprotective efficacy of limonene, highlighting its potential as a therapeutic strategy against pesticide-induced kidney injury. Full article

Acute kidney injury (AKI) is a major global health challenge associated with substantial morbidity, mortality, and progression to chronic kidney disease. Increasing evidence indicates that oxidative stress, mitochondrial dysfunction, inflammatory signaling, regulated cell death, and maladaptive tissue repair play central roles in AKI pathogenesis, yet effective disease-modifying pharmacological therapies remain unavailable. This narrative review critically evaluated current evidence regarding the pharmacological characteristics, molecular mechanisms, and translational potential of alpha-mangostin (AM), the principal prenylated xanthone isolated from the pericarp of Garcinia mangostana L., through a comprehensive synthesis of experimental and mechanistic studies. Available preclinical evidence consistently demonstrates that AM improves renal function and attenuates histopathological injury, particularly in cisplatin-induced nephrotoxicity and glycerol-induced rhabdomyolysis models. These renoprotective effects are primarily associated with suppression of oxidative stress, activation of the Nrf2/HO-1 antioxidant pathway, inhibition of NF-κB-mediated inflammatory signaling, preservation of mitochondrial function, and attenuation of apoptosis. Several emerging pathways may also contribute to AM-mediated renoprotective effects; however, current evidence remains indirect, and their roles require validation in kidney-specific models. Clinical translation remains limited by poor oral bioavailability, insufficient pharmacokinetic data, lack of standardized formulations, and the absence of human clinical trials. Overall, current evidence suggests that AM has preliminary renoprotective potential in experimental AKI models. However, the limited number of available studies, predominance of cisplatin-induced nephrotoxicity models, insufficient pharmacokinetic and safety data, and absence of human clinical studies preclude conclusions regarding its clinical efficacy or translational readiness. Further validation in diverse and clinically relevant AKI models is required before clinical investigation can be considered. Full article

Background: Hyperuricemia has long been linked to the progression of chronic kidney disease (CKD), although the role of serum uric acid (sUA) reduction in kidney preservation remains uncertain. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower sUA levels and exert renoprotective effects, but it is unclear whether these findings are mechanistically related. Methods: Adult patients with type 2 diabetes mellitus and hyperuricemia were included from a retrospective cohort. Patients treated with empagliflozin (n = 70) or dapagliflozin (n = 78) were pooled into a single group and compared with an allopurinol-treated group (n = 66). Exploratory mediation-informed analysis models assessed associations between treatment, changes in sUA (ΔsUA), and changes in estimated glomerular filtration rate (ΔeGFR) at 12 and 36 months. Dose–response and nonlinear associations between ΔsUA and ΔeGFR were additionally examined. Results: At 12 months, SGLT2 inhibitor treatment was associated with greater ΔsUA compared with allopurinol (B = 22.62, p = 0.040); its direct association with ΔeGFR remained significant after adjustment for ΔsUA (B = −6.14, p < 0.001). At 36 months, the association of treatment with ΔsUA was no longer significant, whereas association with ΔeGFR persisted (B = −11.8, p < 0.001). No dose–response or nonlinear relationship was identified between ΔsUA and ΔeGFR, while treatment remained an independent predictor of ΔeGFR at both time points. Conclusions: Reductions in sUA do not appear to mediate the renoprotective effects of SGLT2 inhibitors. The preservation of kidney function associated with SGLT2 inhibitor therapy is likely driven by mechanisms independent of sUA lowering. Full article

Oxybaphus himalaicus Edgew. is a traditional Tibetan medicinal plant used to treat nephritis and edema; however, its active constituents and the molecular mechanisms underlying its renoprotective properties remain poorly elucidated. This study investigated the pharmacological activity and mechanism of Boeravinone A (BA), a major constituent of O. himalaicus, in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A mouse model of LPS-induced AKI and LPS-stimulated RAW264.7 macrophages were used to evaluate the anti-inflammatory and renoprotective effects of BA in vivo and in vitro. Activity-based protein profiling (ABPP) was performed to identify potential molecular targets, followed by validation using isothermal titration calorimetry (ITC), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays. The functional role of the identified target was further examined using shRNA-mediated knockdown and virtual knockout analysis. BA dose-dependently attenuate LPS-induced renal injury and reduced inflammatory responses. Phosphoglycerate kinase 1 (PGK1) was identified as a direct target of BA. Mechanistically, BA activated the Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) pathway through PGK1, enhanced the expression of antioxidant enzymes such as Nqo1, and reduced the production of pro-inflammatory cytokines, including IL-1β and IL-6. Virtual knockout of PGK1 in macrophages further supported its regulatory role in this pathway. These findings suggest that BA exerts renoprotective effects by targeting PGK1 and activating the Keap1-Nrf2 pathway, thereby reducing oxidative stress and inflammation. This study provides a pharmacological basis for the traditional use of O. himalaicus and supports BA as a potential candidate for mechanism-based intervention in AKI. Full article

This study aimed to evaluate the general, hepatoprotective and renoprotective effects of amifostine (AMI) in rats treated with a large, single dose of doxorubicin (DOX), assessed at 7 and 56 days after administration. Rats were divided into six experimental groups: Control (0.9% NaCl intraperitoneally (ip)), amifostine (AMI300, 300 mg/kg (ip)), doxorubicin (DOX6, 6 mg/kg (ip)), doxorubicin (DOX10, 10 mg/kg (ip)), doxorubicin (DOX6, 6 mg/kg (ip)) + amifostine (AMI300, 300 mg/kg (ip) 30 min before DOX6), and doxorubicin (DOX10, 10 mg/kg (ip)) + amifostine (AMI300, 300 mg/kg (ip) 30 min before DOX10). Absolute liver and kidney weights were significantly increased in AMI300 + DOX6-treated animals compared to DOX6 only on day 56. In the group of DOX10-treated rats, AMI300 significantly prevented changes in the number of white blood cells during the four weeks after treatment. The severity of hepatic and renal injuries in the DOX6-treated groups was also significantly less in rats pretreated with AMI300 on day 56 (p < 0.01). Our results indicate that hepatic and renal protection significantly contribute to the successful use of AMI against DOX-induced subacute toxicity in rats. Full article

Diabetic kidney disease (DKD) progression results from complex interactions between metabolic stress, inflammatory activation, maladaptive intracellular signalling, and fibrotic remodelling. While previous studies demonstrated renoprotective effects of cell-specific Adam17 deletion, the impact of global Adam17 deficiency on the integrated renal response to diabetes remains incompletely understood. Here, we investigated the effects of tamoxifen-induced global Adam17 deletion in a streptozotocin-induced murine model of type 1 diabetes. Renal function, structural injury, inflammatory responses, stress-related signalling pathways, and fibrotic remodelling were comprehensively assessed in diabetic Adam17 knockout and control mice. Despite persistent hyperglycemia and ongoing albuminuria, diabetic Adam17 knockout mice exhibited preservation of glomerular filtration rate together with marked attenuation of diabetes-associated kidney injury. Global Adam17 deletion reduced mesangial expansion and structural damage, limited macrophage infiltration and chemokine expression, and significantly attenuated fibrotic remodelling. At the molecular level, Adam17 deficiency was associated with selective modulation of stress-related signalling pathways, including reduced activation of the PI3K/Akt axis and partial preservation of mitochondrial stress regulators, without evidence of generalized suppression of cellular stress responses. Notably, preservation of renal function occurred despite persistent albuminuria, supporting a partial dissociation between glomerular permeability alterations and progressive renal dysfunction. These findings demonstrate that global Adam17 deletion confers robust protection against diabetes-associated kidney injury through coordinated attenuation of inflammatory, stress-related, and profibrotic pathways. Our results extend previous cell-specific observations and highlight the context-dependent role of Adam17 in DKD progression, supporting the concept that integrated Adam17-related signalling may represent a relevant therapeutic target in diabetic kidney disease. Full article

Cisplatin-induced acute kidney injury (AKI) remains a dose-limiting complication in cancer chemotherapy with restricted preventive measures. Carthamus tinctorius L. (safflower) is known to exhibit effective antioxidant and anti-inflammatory properties; however its potential in renoprotective mechanisms remains poorly understood. The present study utilized a cisplatin-induced AKI mouse model to evaluate the renoprotective potential of CT (Carthamus tinctorius) extract. Integrated multi-omics along with in silico and in vivo approaches were used to elucidate the underlying mechanisms of action. The results initially demonstrated a rich phytochemical profile of CT extract characterized by abundant polysaccharides and flavonoids, with Hydroxysafflor Yellow A as a dominant bioactive constituent. In a cisplatin-induced acute kidney injury (AKI) mouse model, CT extract noticeably ameliorated the abnormalities of renal injury, as suggested by improved histopathology, reduced serum creatinine and BUN levels, and regulation of redox homeostasis. Metabolically, CT extract partially reversed AKI-associated disturbances by affecting 21 key metabolites, likely associated with histidine and alanine-aspartate-glutamate biosynthesis, and modulating amino acid and energy metabolism pathways. Concurrently, CT extract improved gut microbial homeostasis, increasing microbial diversity, normalizing the Firmicutes/Bacteroidota ratio, suppressing pathogens, and enriching beneficial Ligilactobacillus. Network pharmacology and molecular docking identified AKT1, RELA, MAPK, and TP53 as central targets of core compounds (rutin and kaempferol derivatives), apparently targeting the PI3K-AKT and RELA (NF-kappaB) hubs. These results suggested that the renoprotective effects of CT extract are associated with transcriptional upregulation of the PI3K/Akt/Nrf2 pathway-related genes, increased expression of antioxidant genes (Ho-1, Sod1), and reduced expression of pro-inflammatory mediators (RelA, Cdk2) in the cisplatin-induced AKI mouse model. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated significant renoprotective effects in patients with chronic kidney disease. However, kidney transplant recipients have been excluded from major randomized trials, and evidence in non-diabetic transplant patients remains limited. This study aimed to investigate the potential effects of SGLT2 inhibitors in non-diabetic kidney transplant recipients. Methods: Kidney transplant recipients were screened retrospectively and divided into two groups based on SGLT2 inhibitor use. A total of 18 non-diabetic patients receiving SGLT2 inhibitors (Group 1) were compared with 30 matched controls (Group 2). Patients were followed at baseline, 3, 6, and 12 months. Proteinuria, serum creatinine, eGFR, uric acid, and tacrolimus levels were analyzed. Results: Baseline demographic and biochemical characteristics were similar between groups. In Group 1, proteinuria decreased by 20% at 6 months and 26% at 12 months compared with baseline. The reduction in proteinuria from baseline to 6 months was significantly greater in Group 1 than in controls (p = 0.037). No significant changes were observed in serum creatinine, eGFR, tacrolimus levels, or infection-related adverse events between groups. Conclusions: SGLT2 inhibitors may confer an early antiproteinuric benefit in non-diabetic kidney transplant recipients without apparent adverse effects on renal function or safety. Larger prospective studies are needed to confirm long-term effects. Full article

Diabetic nephropathy (DN) is a severe diabetic complication with substantial clinical burden. The complex pathogenesis of DN has hindered the development of targeted therapies, creating an urgent need to develop novel strategies that directly address its underlying inflammatory and fibrotic mechanisms. Coreopsis tinctoria (CE) is an edible plant rich in polyphenols, but its mechanism against DN remains understood. An integrated framework combining network pharmacology and machine learning was developed to prioritize active polyphenols and their targets. A multi-layer perceptron classifier, trained on 3.16 million compound–target pairs from Binding DB, predicted interactions between 36 CE polyphenols and 12,030 DN-associated genes. The top 100 targets were subjected to KEGG enrichment analysis, and the identified pathways were validated in a high-fat diet/STZ-induced DN rat model. The MLP model achieved superior performance (AUC-ROC = 0.9219, AP = 0.9592). Five lead polyphenols (flavonoids/chalcones) showed high predicted activity. KEGG analysis revealed enrichment in PI3K-Akt, calcium signaling, metabolic pathways, and cellular senescence. In vivo, CE treatment (150–600 mg/kg/day) dose-dependently improved glucose/lipid metabolism and renal function, and ameliorated histopathological damage, including glomerular hypertrophy, fibrosis, and mesangial expansion. Mechanistically, CE suppressed NFκB/TGFβ/Smad signaling, restored PPARγ and Nrf2/HO-1/FoxO1 antioxidant defenses, and inhibited apoptosis via Bcl-2/Bax regulation. CE exerts multi-target renoprotective effects through coordinated modulation of metabolic, inflammatory, fibrotic, and antioxidant pathways, supporting its potential as a functional food ingredient for DN management. Full article

Mineralocorticoid receptor (MR) overactivation is a key driver of inflammation, fibrosis, and organ cross-talk across cardiorenal disease. Finerenone, a selective non-steroidal MR antagonist, has demonstrated robust renoprotective and cardioprotective benefits in patients with chronic kidney disease (CKD) and type 2 diabetes in large randomized clinical trials. Beyond its established role in diabetic kidney disease, emerging preclinical and clinical data suggest potential systemic effects through the attenuation of MR-driven inflammatory and fibrotic pathways. These include signals related to heart failure outcomes, atrial remodeling, pulmonary vascular biology, retinal microvascular integrity, and metabolic dysfunction. However, much of the evidence beyond established cardiorenal indications remains exploratory, based on preclinical studies, subgroup analyses, and post hoc evaluations. This review provides a critical synthesis of the established clinical evidence supporting finerenone in CKD and cardiovascular disease. It examines emerging, hypothesis-generating data regarding its potential systemic effects beyond diabetic kidney disease. Full article

Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are major contributors to global morbidity and mortality, with disease progression being closely linked to persistent inflammation, oxidative damage, and apoptotic pathways. Icariin (ICA), a bioactive flavonoid compound isolated from Epimedium brevicornum Maxim, has attracted considerable interest because of its diverse pharmacological properties. We evaluated the effect of ICA on streptozotocin (STZ)-induced diabetic rats with or without adenine-induced CKD. This combined model reproduces several key structural and functional characteristics observed in human diabetic kidney disease and advanced CKD. Methods: Male Wistar rats were allocated to five treatment groups and followed for 35 days. Group 1 served as the untreated control and received standard chow; Group 2 was administered streptozotocin (STZ); Group 3 received STZ together with icariin (ICA); Group 4 received a combination of adenine and STZ; and Group 5 was treated with adenine, STZ, and ICA. ICA was administered at a dose of 200 mg/kg by oral gavage. Biochemical, oxidative stress and inflammatory markers were assessed. Results: Rats treated with STZ, with or without adenine, exhibited significant hyperglycemia, elevated plasma levels of cystatin C and indoxyl sulphate, increased urinary levels of N-acetyl-β-D-glucosaminidase (NAG) and NAG/creatinine ratio, and reduced creatinine clearance. Additionally, there were significant decreases in renalase activity and urine osmolality, significant increases in interleukins IL-1β and IL-6 and TNF-alpha levels, and a decrease in IL-10 level. Oxidative stress biomarkers were also significantly impaired in both groups, along with significant renal histopathological changes. ICA significantly ameliorated these alterations in both experimental groups. Conclusions: These findings demonstrate that ICA exerts renoprotective and anti-inflammatory effects in a clinically relevant model of advanced diabetic CKD. Further studies are warranted to elucidate the underlying mechanisms and determine the translational relevance of these findings. Full article

Background: Gentamicin-induced nephrotoxicity limits clinical pharmacotherapy and involves multiple converging stress-response pathways. Ellagic acid (EA) has renoprotective potential, yet its role in coordinating endoplasmic reticulum (ER) stress-mediated apoptosis, autophagy, and inflammation remains unclear. We hypothesized that EA co-treatment would protect the kidney by modulating ER stress-dependent pathways and associated inflammatory and adaptive signaling. Methods: For an integrated mechanistic analysis in a rat model of gentamicin nephrotoxicity, 40 male Sprague-Dawley rats were assigned to control, gentamicin (100 mg/kg), EA (100 mg/kg), and gentamicin + EA groups for 14 days. Renal function, oxidative stress, inflammatory mediators, ER stress markers, apoptosis, autophagy, tubular injury markers, and histopathological changes were assessed. Results: Gentamicin induced renal dysfunction, tubular injury, and ER stress across all unfolded protein response (UPR) branches (IRE1α, PERK, ATF6), C/EBP homologous protein (CHOP)-associated apoptosis, dysregulated autophagy, and upregulated kidney injury molecule-1 (KIM-1). A selective inflammatory signature was observed, with increased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), whereas tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) remained unchanged. Co-administration of ellagic acid with gentamicin significantly improved renal function markers compared to the gentamicin group. In contrast, ellagic acid alone did not show significant differences compared to the control group. Notably, gentamicin induced compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, while ellagic acid co-treatment attenuated this compensatory upregulation, likely secondary to reduced oxidative stress burden. Conclusions: This study provides integrated evidence that ER stress is closely associated with gentamicin nephrotoxicity. The key novel findings include selective suppression of IL-6, modulation of the apoptosis-autophagy balance, and attenuation of Nrf2/HO-1 signaling without direct reactive oxygen species (ROS) scavenging, demonstrating a multi-target framework for EA’s renoprotective effects. These findings suggest that ellagic acid mitigates renal injury in a context-dependent manner rather than confirming a direct causal mechanism. Full article

Excessive administration of epinephrine and norepinephrine in critically ill patients may trigger a catecholamine storm and contribute to acute kidney injury (AKI) through activation of β-adrenoceptor signaling. Although clinical observations link high-dose catecholamine exposure to increased AKI risk, experimental models and mechanistic studies remain limited. We established a rodent model of combined epinephrine and norepinephrine infusion to investigate the renoprotective effects of subtype-selective β-adrenoceptor blockers. Animals received the β1-selective blockers metoprolol or atenolol, or the β2-selective blocker ICI 118,551. β1-adrenoceptor blockade, particularly with metoprolol, significantly attenuated renal histopathological injury and improved biochemical markers of kidney dysfunction. These protective effects were associated with suppression of ferroptosis-related pathways in the renal cortex. Atenolol partially improved biochemical parameters but did not significantly reduce tubulointerstitial damage, whereas β2-adrenoceptor blockade conferred limited functional benefit despite modest morphological improvement. Collectively, our findings indicate that β1-adrenoceptor activation plays a critical role in catecholamine-induced AKI by promoting ferroptosis. Targeting β1-adrenoceptors, especially with metoprolol, may represent a potential therapeutic strategy for preventing renal injury during catecholamine storms. Full article