The role of trace elements, including zinc, selenium, iron, copper, cadmium, lead, and other essential or toxic elements, in diabetic kidney disease (DKD) has become increasingly recognized because of their effects on oxidative stress, metabolic regulation, and renal dysfunction. However, a comprehensive bibliometric analysis of research trends and molecular insights into these interactions is still lacking. This study presents a bibliometric analysis of publications from 1981 to 2025 using WoSCC, and data were analyzed using VOSviewer, CiteSpace, and the Bibliometric Online Analysis Platform (http://bibliometric.com/) to generate scientometric visualizations. A thorough analysis and visualization of 373 research papers on the relationship between trace elements and DKD published between 1981 and 2025 were conducted, revealing emerging research hotspots and trends. Initially, there were very few studies in this field. However, a significant increase in research interest followed in subsequent years, ultimately peaking in 2025 with 70 publications. Research in this field is mainly concentrated in Asia, particularly in China, which has the highest number of corresponding authors. International collaboration has also greatly increased citation impact. Key research topics include oxidative stress, metabolic disorders, and recently ferroptosis and cuproptosis as new molecular mechanisms in DKD. This study provides a data-driven analysis of the evolving research landscape, offering insights into the future directions of trace element-related DKD studies, particularly in understanding the transition from environmental toxicology to molecular intervention.

Astragaloside IV (AS-IV) has demonstrated efficacy in ameliorating proteinuria and attenuating renal tubular damage in preclinical diabetic nephropathy (DN) models. Despite these multi-target benefits, the molecular mechanisms underlying its podocyte-protective effects remain largely uncharacterized, particularly its potential epigenetic regulatory capacity within glomerular cells. This study aimed to test the hypothesis that AS-IV protects against DN by activating the deacetylase sirtuin 6 (SIRT6). Specifically, AS-IV activates SIRT6, which deacetylates Histone H3 at Lysine 9 (H3K9) at the Notch1 promoter, thereby suppressing Notch1 expression. This suppression is expected to enhance autophagy and reduce apoptosis, ultimately repairing renal filtration barrier injury. A murine model of DN was induced with streptozotocin and a high-fat diet. To simulate diabetic damage, MPC-5 podocytes were subjected to high glucose (HG, 33 mM). Renal function metrics were extensively evaluated, and glomerular histopathological and ultrastructural changes were assessed by hematoxylin and eosin staining and electron microscopy. Subsequently, downstream mechanisms involving podocyte autophagy and apoptosis were investigated by immunofluorescence staining and Western blotting. To confirm that SIRT6 directly regulates Notch1 transcription via histone deacetylation, our study utilized chromatin immunoprecipitation (ChIP). Our results showed that AS-IV treatment alleviated renal biochemical and pathological abnormalities in DN mice and attenuated podocyte injury, evidenced by restoring nephrin and podocin expression and reducing glomerular basement membrane thickness (p < 0.01). Functionally, AS-IV treatment reversed HG-induced podocyte apoptosis and autophagy dysfunction (p < 0.01). Mechanistically, AS-IV was confirmed to directly bind to SIRT6 (Kd = 0.164 μM). ChIP assays demonstrated increased SIRT6 occupancy and consequently reduced H3K9ac enrichment at the Notch1 promoter (p < 0.01). In summary, AS-IV may ameliorate DN by activating the SIRT6/H3K9ac/Notch1 epigenetic axis, providing a strong molecular basis for AS-IV as a promising therapeutic agent against DN.

Diabetes mellitus can cause progressive renal injury characterized by oxidative stress, inflammation, and impaired renal function. This study investigated the kidney- and cell-protective potential of acarbose-guar gum solid dispersion (AGSD-3) using in vitro and in vivo diabetic models. In BHK-21 cells, AGSD-3 showed improved biocompatibility, with higher cell viability (65.54 ± 0.41%) than acarbose (56.67 ± 0.24%) and reduced lactate dehydrogenase release (7.29 ± 0.13%) at 100 µg/mL. Under high-glucose conditions, AGSD-3 significantly reduced lipid peroxidation and enhanced superoxide dismutase, catalase, and glutathione S-transferase activities (p < 0.001). In diabetic rats, AGSD-3 (50 mg/kg) significantly improved renal function, reducing serum creatinine, urea, and uric acid to 0.45 ± 0.02, 36.00 ± 0.96, and 2.00 ± 0.02 mg/dL, respectively, and normalized relative kidney weight. Histopathological findings further supported restoration of renal architecture. AGSD-3 enhanced renal antioxidant status, with increased SOD, catalase, and GST activities, while reducing nitric oxide, xanthine oxidase, and acetylcholinesterase activities (p < 0.001). Furthermore, AGSD-3 reduced TNF-α and IL-6 while increasing IL-10 levels. Overall, AGSD-3 exhibited antioxidant, anti-inflammatory, and renoprotective effects, supporting its potential as an improved acarbose-based formulation for diabetes-associated renal injury.

Aldosterone, a key component of the renin-angiotensin-aldosterone system (RAAS), plays a central role in sodium balance, vascular tone, blood pressure control, and cardiovascular remodeling. Dysregulation of aldosterone mechanism, including excessive production, deficiency, and inappropriate receptor activation, represents a significant contributor to cardiovascular and renal disease which is often underrecognized. Aldosterone dysregulation may manifest as primary aldosteronism that is increasingly identified as a common cause of secondary hypertension, or by secondary hyperaldosteronism that reflects maladaptive responses in common clinical conditions such as heart failure and liver cirrhosis. Conversely, hypoaldosteronism, particularly in diabetic nephropathy, predisposes to hyperkalemia and metabolic acidosis. Furthermore, aldosterone dysregulation can be observed in many clinically important and common patient phenotypes such as older patients, obese, and patients with diabetes where the elevated levels of aldosterone can contribute to poor blood pressure control and development of target organ damage particularly at the cardiac, vascular, and renal level. Beyond circulating levels of aldosterone itself, mineralocorticoid receptor (MR) overactivation in the absence of elevated aldosterone highlights the complexity of tissue-specific signaling. This review summarizes the spectrum of aldosterone dysregulation, delineates key patient phenotypes, and discusses diagnostic and therapeutic implications with a focus on cardiovascular outcomes. Recognizing aldosterone dysregulation as a systemic cardio-renal-metabolic disorder has important implications for risk stratification and targeted therapies.

Ubiquitin-specific protease 22 (USP22), which was found to serve as a specific deubiquitinase of hypoxia-inducible factor-1α (HIF-1α), plays an important role in diabetic nephropathy (DN) pathological mechanisms, but currently available therapies remain insufficient to fully arrest its progression. Fucoidan (FO), a marine-derived fucose-rich sulfated polysaccharide, has been reported to treat acute renal damage and chronic renal failure by ameliorating ferroptosis. But whether FO could modulate USP22/HIF-1α in the pathogenesis of DN is unknown. Here, db/db mice were treated with the USP22 inhibitor S02 or FO for 13 weeks, and renal injury was subsequently characterized through biochemical, histological, and molecular analyses. S02 or FO administration markedly alleviated renal structural injury, improved fasting blood glucose and renal functional indices, and reduced oxidative stress, iron deposition, and the expression of profibrotic and proinflammatory mediators in diabetic kidneys. Mechanistically, protective effects were associated with suppression of USP22 by deubiquitinating HIF-1α, and amelioration of ferroptosis-related renal damage. Notably, inhibition of USP22 by FO recapitulated the renoprotective phenotype. Together, these findings suggest that FO mitigates DN by constraining USP22/HIF-1α-driven ferroptotic and oxidative injury, thereby supporting its potential as a natural therapeutic candidate for DN.

Diabetic kidney disease (DKD) progression is driven by residual inflammation, potentially exacerbated by volatile organic compounds (VOCs). However, the impact of xylene exposure on the DKD immune microenvironment remains unclear. We evaluated the association between urinary VOC metabolites and DKD prevalence using NHANES data. Network toxicology and bulk transcriptomics (GSE142025) were integrated to identify core targets and profile immune infiltration. Single-cell RNA sequencing (GSE209781) validated macrophage heterogeneity and hub gene dynamics, and molecular docking assessed xylene-receptor binding affinities. Elevated urinary xylene metabolite (DPMA) correlated with increased DKD odds (OR = 4.03, 95% CI: 1.80-9.00). Multi-omics identified ITGAM, CSF1R, and CTSS as primary hub genes enriched in immune pathways. Both bulk and single-cell RNA sequencing analyses revealed that DKD tissues exhibited M2-like macrophage enrichment and an expansion of fibrotic SPP1+ subsets. This altered microenvironment positively correlated with hub gene upregulation along the macrophage developmental trajectory. Molecular docking suggested potential binding between xylene isomers and these receptors (binding free energies: -4.7 to -5.9 kcal/mol). Environmental xylene exposure is independently associated with higher DKD odds. These findings generate the hypothesis that xylene may interact with specific macrophage receptors (ITGAM, CSF1R, CTSS), potentially promoting M2-like macrophage polarization and fibrotic remodeling. This putative environmental-immunological axis warrants further experimental validation.

Diabetic kidney disease (DKD) is a major cause of chronic kidney diseases. Panoptosis has emerged as a key contributor to renal injury. However, the specific panoptosis-related genes (PRGs) that drive diabetic tubular injury remain unknown. TNFSF10, a known regulator of apoptosis and inflammation, has been linked to podocyte injury in DKD, but its role in diabetic tubular injury remains unknown. To address this, we integrated weighted gene co-expression network analysis, machine learning algorithms, and clinical data from the Nephroseq database to identify PRGs associated with DKD. The biological function of the identified hub gene was further characterized by integrating single-cell and single-nucleus RNA sequencing data with analytical frameworks for cellular communication, trajectory inference, and regulatory network. In this study, we identified TNFSF10 as a conserved and robust hub PRG for DKD. TNFSF10 expression was significantly upregulated in DKD kidneys and inversely correlated with glomerular filtration rate. TNFSF10[high] kidneys exhibited elevated fibrosis and inflammation scores. scRNA/snRNA analysis revealed its predominant expression in injured proximal tubular cells. Importantly, TNFSF10[+] proximal tubular cells showed transcriptomic signatures consistent with panoptosis activation and inflammatory signaling, along with enhanced ligand-receptor interactions with fibroblasts and immune cells. Consistently, TNFSF10 treatment induced cell death and increased the expression of multiple inflammatory genes in vitro. Collectively, our results suggest that TNFSF10 is associated with tubular injury and kidney fibroinflammation in DKD. These exploratory findings suggest it may represent a promising candidate for DKD, and further in vivo functional validation is required to confirm its diagnostic and therapeutic potential.