Shimin Jiang

Podocyte injury is a central pathological event in diabetic kidney disease (DKD), but the mitochondrial regulatory mechanisms underlying podocyte dysfunction remain incompletely defined. We integrated single-nucleus RNA-seq data from human renal biopsies in GSE195460 with podocyte-specific differential expression, functional enrichment, mitochondrial gene annotation, co-expression network analysis, machine learning feature selection, pseudotime analysis, in silico knockout, transcription factor enrichment, motif analysis, and molecular docking; findings were externally evaluated in GSE209781. Podocytes showed prominent disease-associated transcriptomic perturbation, with 677 exploratory cell-level differentially expressed genes and enrichment of cytoskeletal, adhesion, developmental, oxidative phosphorylation, and metabolic pathways. Thirty-one mitochondrial-related differentially expressed genes were identified, and OXR1 was prioritized as a candidate regulatory hub based on consistent downregulation, network centrality, machine learning selection, and external validation. HNF4A was predicted as an upstream regulator linked to OXR1 and other mitochondrial targets. In silico OXR1 perturbation increased the predicted injured-state probability from 15% to 82%, while promoter motif analysis provided additional computational support for a putative HNF4A–OXR1 regulatory relationship. These findings highlight OXR1 as a candidate associated with podocyte mitochondrial dysfunction in DKD and suggest a putative HNF4A–OXR1 regulatory relationship.

Diabetic kidney disease (DKD) progression is closely linked to the loss of podocyte homeostasis, driven in part by intracellular lipid accumulation and impaired autophagic clearance. This study identifies angiopoietin‐like protein 4 (ANGPTL4) as a potential regulator of podocyte lipophagy in DKD. In renal biopsies from patients with DKD, ANGPTL4 is upregulated in podocytes, and its expression is associated with greater proteinuria and more rapid renal function decline. In immortalized human podocytes, exposure to high glucose and palmitic acid (HGPA) increases both intracellular and secreted ANGPTL4, impairs autophagic flux, and promotes lipid droplet accumulation. Mechanistically, ANGPTL4 overexpression reduces TFEB nuclear localization, increases lysosomal pH, and decreases cathepsin B and lysosomal acid lipase activities, consistent with impaired terminal lysosomal lipid degradation. Conversely, ANGPTL4 knockdown restores autophagic and lysosomal programs under HGPA conditions. Recombinant human N‐terminal ANGPTL4 fragment reproduces several TFEB‐localization, lysosomal, and lipophagic defects, whereas extracellular neutralization partially reverses these changes. Expression of constitutively active TFEB‐S211A restores lysosomal function and lipid clearance and attenuates profibrotic remodeling. Collectively, these findings support an ANGPTL4–TFEB‐associated lysosome–lipophagy pathway linking diabetic metabolic stress to defective lipid clearance and podocyte injury.

Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic susceptibility, transcriptomic, and proteomic signatures, remain to be elucidated. We conducted a large-scale prospective cohort study including 330,002 UK Biobank participants with an average follow-up of 13.0 years. Annual average concentrations of PM_2.5, PM_2.5-10, PM₁₀, NO₂, and NO_X were assessed. Cox proportional hazards models were applied to estimate CKD risk associated with long-term air pollution exposure. We further evaluated non-linear relationships using restricted cubic splines (RCS), potential mediators via mediation analyses, and CKD susceptibility through additive interaction analyses with baseline comorbidities and polygenic risk scores (PRS). Additionally, transcriptome-wide association study (TWAS) and proteome-wide two-step Mendelian randomization (MR) were integrated to explore potential molecular pathways. Higher exposures to PM_2.5 (HR: 1.36, 95% CI: 1.22-1.51, per 5 µg/m³), PM_2.5-10 (HR: 1.25, 95% CI: 1.07-1.46, per 5 µg/m³), PM₁₀ (HR: 1.20, 95% CI: 1.06-1.36, per 10 µg/m³), and NO_X (HR: 1.04, 95% CI: 1.02-1.07, per 20 µg/m³) were significantly associated with increased CKD risk, whereas NO₂ showed no significant association (HR: 0.98, 95% CI: 0.95-1.00, per 10 µg/m³). RCS revealed non-linear relationships for PM_2.5-10 and PM₁₀. Mediation analyses indicated that incident hypertension and type 2 diabetes mellitus (T2DM) acted as potential mediators in these associations. Crucially, additive interaction analyses revealed that participants with pre-existing hypertension or type 1 diabetes mellitus (T1DM) were significantly more vulnerable to specific pollution-driven CKD. Compared to individuals with low genetic risk and low air pollution exposure, those with both high genetic risk and high exposure exhibited the highest CKD risk, demonstrating a clear gradient effect across categories. TWAS identified shared genes potentially linking air pollutants with CKD, including upregulated transcripts (STX2, PHOSPHO2, NECAB3) and downregulated transcripts (CDK3, MEIOB, NDUFAF1, CRIPAK). Furthermore, proteome-wide MR analyses identified ALDH3A1, F12, and SNCG as potential risk proteins, and GNLY and MEGF10 as protective proteins. This study provides comprehensive evidence that long-term air pollution exposure is associated with increased CKD risk and offers exploratory insights into the potential molecular pathways underlying this association, advocating the incorporation of renal health considerations into air quality control policies.

The Cholesterol, High-Density Lipoprotein, and Glucose (CHG) index is a recently proposed composite metric, but its utility in predicting the development a

Background: This study aimed to differentiate whether diabetic nephropathy (DN) is complicated by minimal change disease (MCD) through the differences in podocyte foot process morphology, and subsequently establish an Artificial Intelligence-Assisted (AI-assisted) Diagnostic Model through machine learning of renal tissue electron microscopy images. Methods: Patients diagnosed with DN with nephrotic syndrome and treated in our hospital from January 2014 to December 2023 were selected. Patients were divided into the DN group and the DN with MCD group (DN+MCD group). Podocyte morphology’s diagnostic value was assessed by measuring foot process width and quantifying slit diaphragm changes via Nephrin immunohistochemical staining. This study pioneers developing a machine learning-powered diagnostic model based on renal electron microscopy imaging to differentiate DN cases with or without concurrent MCD. Results: In 51 patients, DN+MCD patients exhibited wider podocyte foot processes and reduced Nephrin expression compared to DN. A total of 622 electron microscopy images were used for model establishment and internal validation, while 225 electron microscopy images were used for external validation. A model based on Mobilenetv2 was successfully established, achieving a maximum accuracy of 93.3% in differentiating whether DN is complicated by MCD using a single image. When at least 11 random images were input, stable reports were obtained with an accuracy of 98%. External validation showed that the model had good sensitivity and specificity in differentiating whether DN is complicated by MCD (100%, 83.33%). Conclusion: Podocyte foot process morphology has diagnostic value in differentiating whether DN is complicated by MCD. Our AI model addresses the unmet clinical need for reliable differentiation between DN with and without concurrent MCD. Additionally, it establishes a foundational framework for AI-powered analysis of renal imaging data to improve disease diagnosis and prognosis prediction.

The role of complement system in late stage of IgA nephropathy (IgAN) remains unknown. We therefore investigated the effects of complement system on worsening kidney function in advanced (stage 4 CKD) IgAN. Renal specimens of 69 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2021, were stained using immunofluorescence (IF) and immunohistochemistry (IHC) for glomerular complement components. The primary outcome was progression to end-stage renal disease (ESRD). Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 18.0 months, 26 (37.7%) patients progressed to ESRD and none died. C1q and C3 deposition were detected in 12 and 66 patients, respectively. Higher eGFR [hazards ratio (HR), 0.852, 95% confidence interval (CI), 0.756–0.959; P = 0.008], higher C3 intensity (HR, 2.955, 95%CI, 1.063–8.220; P = 0.038) and T1-2 score (HR, 2.576, 95%CI, 1.205–5.576, P = 0.015) were predictive of time to ESRD in CKD 4 stage IgAN. Significant expressions of C1q (P = 0.005), C4d (P < 0.001), factor B (P < 0.001), C3 (P = 0.042) and C5b-9 (P = 0.004) were identified in ESRD group than in non-ESRD group by IHC, while MBL expression was low. Although they were not associated with baseline 24 h-UP, higher factor B and C1q expressions were both correlated with a lower baseline eGFR (P < 0.001 and = 0.04, respectively) and the deterioration of kidney function during follow-up (P = 0.046 and 0.015, respectively). Complement deposition in IgAN patients with stage 4 CKD portends a faster deterioration of kidney function. Activation of classical and alternative complement pathways plays a major role in this stage.

Mesenchymal stem cell derived exosomes (MSC-Exos) demonstrate beneficial effects on wound healing via anti-inflammatory and angiogenic properties. Chitosan (CS) exhibits excellent biocompatibility and accelerates cellular migration, adhesion, and proliferation. The ions released from bioactive glass (BG) and titanium dioxide (TiO₂) nanoparticles exhibit sustained angiogenic and antibacterial potency. In this study, CMCS-CEBT hydrogel was synthesized from exosomes encapsulated carboxymethyl chitosan (CMCS), chitosan nanoparticles (CS-NPs), BG, and TiO₂ nanoparticles for a preliminary evaluation of its impacts on the treatment of full-thickness skin defects, diabetic wounds, and burn skin injury due to burns. In vitro analysis indicated that the hydrogel exhibits excellent cell compatibility, stimulates endothelial cell adhesion and proliferation, and presents anti-inflammatory, angiogenic, and antibacterial activities. In vivo, the composite hydrogel dressing accelerated a wound healing acceleration effect, stimulated angiogenesis, and increased collagen deposition and the expression of anti-inflammatory factors. This innovative composite hydrogel dressing as a potential clinical therapy, utilizing bioactive materials, holds promise as a potential clinical therapy that aims to facilitate the regeneration of acute and chronically damaged skin tissue.

Objective: To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs. Methods: We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82–0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85–1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66–0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77–0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76–0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function. Conclusions: Finerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.