Podocyte injury or dysfunction can lead to proteinuria and glomerulosclerosis. Zonula occludens 1 (ZO-1) is a tight junction protein which connects slit diaphragm (SD) proteins to the actin cytoskeleton. Previous studies have shown that the expression of ZO-1 is decreased in chronic kidney disease (CKD). Thus, elucidation of the regulation mechanism of ZO-1 has considerable clinical importance. Triptolide (TP) has been reported to exert a strong antiproteinuric effect by inhibiting podocyte epithelial mesenchymal transition (EMT) and inflammatory response. However, the underlying mechanisms are still unclear. We found that TP upregulates ZO-1 expression and increases the fluorescence intensity of ZO-1 in a puromycin aminonucleoside (PAN)-induced podocyte injury model. Permeablity assay showed TP decreases podocyte permeability in PAN-treated podocyte. TP also upregulates the DNA demethylase TET2. Our results showed that treatment with the DNA methyltransferase inhibitors 5-azacytidine (5-AzaC) and RG108 significantly increased ZO-1 expression in PAN-treated podocytes. Methylated DNA immunoprecipitation (MeDIP) and hydroxymethylated DNA immunoprecipitation (hMeDIP) results showed that TP regulates the methylation status of the ZO-1 promoter. Knockdown of TET2 decreased ZO-1 expression and increased methylation of its promoter, resulting in the increase of podocyte permeability. Altogether, these results indicate that TP upregulates the expression of ZO-1 and decreases podocyte permeability through TET2-mediated 5 mC demethylation. These findings suggest that TP may alleviate podocyte permeability through TET2-mediated hydroxymethylation of ZO-1.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal failure. Ferroptosis, an iron-dependent form of lipid peroxidation, contributes to DKD

Introduction: Cryofibrinogen-associated glomerulonephritis (CF-GN) is a rare disease that lacks comprehensive research and requires further investigation to improve our understanding of its pathophysiology.Methods: Based on the morphological findings from a kidney biopsy and blood tests, an elderly patient was diagnosed with CF-GN. Biological materials obtained from peripheral blood were utilized to treat cultured mesangial cells and mice.Results: The patient presented with nephrotic syndrome and chronic kidney failure. The biopsy revealed a membranoproliferative glomerulonephritis pattern with distinct substructures and positive fibrinogen staining. Cryofibrinogen was detectable under cold conditions, and monoclonal immunoglobulin (MIg) was exclusively identified within cryoprecipitates. Genetic analysis uncovered an intronic mutation. The patient partially responded to immunosuppressive therapy, but later relapsed with paraproteinemia, and the MIg was detected to have cryoactivity. To investigate the pathophysiology of CF-GN further, its cryoactivity was detected when mixing the serum (with or without MIg) with healthy control plasma. When exposed to the patient’s cryoprecipitates, cultured mesangial cells showed significant proliferation, phagocytosis of fibrinogen, and lysosomal degeneration. Injection of these cryoprecipitates into mice induced proliferative glomerulonephritis and other organ damage.Conclusion: This study provides valuable insights into the diagnosis, treatment, and pathophysiology of CF-GN with paraproteinemia. The identification of the complex of cryofibrinogen and MIg as a potential mechanism of glomerular damage shed light on the pathogenesis of this rare disease.

Kidney disorders have become a prevalent global public health crisis, accompanied by soaring morbidity and insufficient therapeutic regimens in clinical practice. Celastrol, a biologically active pentacyclic triterpenoid isolated from Tripterygium wilfordii , is well documented to exert powerful anti-inflammatory, antioxidant, and anti-fibrotic bioactivities. A growing body of preclinical data confirms that celastrol yields remarkable renoprotective outcomes in a broad spectrum of renal disease models, encompassing diabetic kidney disease, IgA nephropathy, chronic kidney disease, as well as acute kidney injury. Mechanistically, celastrol alleviates renal inflammatory infiltration, oxidative stress injury, and pathological fibrotic remodeling through the synergistic regulation of pivotal signaling axes, such as PI3K/Akt/NF-κB, p38 MAPK/NF-κB, Nrf2/GPX4, and SIRT1/EZH2/Wnt/β-catenin pathways. However, a narrow therapeutic index and systemic toxicity greatly hinder its clinical translation. To address this, kidney-targeted delivery systems —including nanoparticle-based carriers ( e.g ., liposomes) and microneedle patches—have been developed to increase renal drug accumulation and reduce off-target toxicity. Further efforts should focus on elucidating context-dependent mechanisms, optimizing carrier design, and advancing clinical trials to fully unlock the therapeutic potential of celastrol against kidney diseases.