Search Results (79)

Podocytes are highly specialized, terminally differentiated epithelial cells essential for maintaining the glomerular filtration barrier. Their limited regenerative capacity and high metabolic demands render them particularly susceptible to aging-related stress. Accumulating evidence indicates that podocyte aging, characterized by cellular senescence, mitochondrial dysfunction, autophagy impairment, and epigenetic alterations, significantly contributes to the pathogenesis of diverse glomerular diseases collectively termed podocytopathies. These include focal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, diabetic kidney disease, and lupus nephritis. This review discusses the cellular and molecular mechanisms driving podocyte aging and explores how these alterations predispose to podocyte injury, loss, and dysfunction, ultimately culminating in podocytopathies. Furthermore, we highlight current and emerging therapeutic strategies that aim to preserve podocyte health by targeting aging-associated pathways. Understanding podocyte aging elucidates mechanisms of chronic kidney disease progression and identifies novel therapeutic strategies for age-specific interventions in podocytopathies. Full article

Podocyte injury is a central event in the pathogenesis of diabetic nephropathy (DN). We conducted a systematic review across four major databases, identifying 7769 records and including 130 studies that met predefined eligibility criteria. Methodological quality was assessed with Joanna Briggs Institute tools, yielding a mean score of 81.3%, indicating overall moderate-to-high rigor despite design-contingent limitations. Publication activity was sparse until 2018 but increased markedly thereafter, with more than 80% of studies published between 2019 and 2025. Temporal analyses confirmed a strong positive trend (p = 0.86, p < 0.0001), reflecting the rapid expansion of this field. Study designs evolved from early human-only descriptions to integrated multi-model approaches combining human tissue, animal experiments, and in vitro systems, thus balancing clinical relevance with mechanistic exploration. Geographically, Asia emerged as the leading contributor, complemented by increasing multinational collaborations. Mechanistic synthesis highlighted five reproducible pillars of podocyte injury: slit-diaphragm and adhesion failure, mTOR–autophagy–ER stress disequilibrium, mitochondrial and lipid-driven oxidative injury, immune, complement, and inflammasome activation, and epigenetic and transcriptomic reprogramming. Collectively, these findings underscore a convergent mechanistic cascade driving podocyte dysfunction, while also providing a framework for therapeutic interventions aimed at restoring barrier integrity, metabolic balance, and immune regulation in DN. Full article

Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME. To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles. In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate. In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling. These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies. Full article

Diabetic nephropathy is a major challenge in medicine. While a variety of mechanisms underlie the onset and progression of diabetic nephropathy, oxidative stress is critical because it promotes inflammation and creates a vicious cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial–mesenchymal transition, tubular atrophy, and proteinuria. There are various treatments for diabetic nephropathy, and each has its own limitations. Although the exact mechanisms by which polyphenols suppress diabetic nephropathy have not been elucidated, they may have antioxidant, anti-inflammatory, antifibrotic, and/or anti-apoptotic effects. They may also suppress endoplasmic reticulum stress and ameliorate mitochondrial dysfunction and dyslipidemia. Dietary polyphenols may be able to prevent the onset and slow the progression of diabetic nephropathy; they include resveratrol, quercetin, isoflavones, catechins, and anthocyanidins and have antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic effects through multiple molecular targets. Furthermore, they have shown few side effects. However, further research is needed to fully elucidate the molecular mechanisms by which polyphenols exert their effects and to clarify their optimal therapeutic use. In this review, we summarize reports published in the past five years regarding their effects on diabetic nephropathy and provide an overview of the potential of polyphenols. Full article

Focal segmental glomerulosclerosis (FSGS) is a histopathological pattern of segmental glomerulosclerosis that arises from diverse primary and secondary causes. Primary (idiopathic) FSGS is rare and is often linked to intrinsic podocyte injury, while secondary forms are more prevalent and may reflect adaptative, toxic, genetic, or viral etiologies. This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease. The pathophysiology is multifactorial and includes direct podocyte injury (e.g., genetic defects, mechanical or toxic injury), immune-mediated processes (e.g., circulating permeability factors, inflammatory mediators), and metabolic disturbances. In particular, disturbance of lipid metabolism, including intracellular cholesterol accumulation in podocytes, have been implicated as a contributory mechanism in podocyte dysfunction and progression of disease in proteinuric/nephrotic presentations and in specific disease subtypes. Diagnosis relies on clinical assessment, laboratory testing, and histological examination, with kidney biopsy remaining the gold standard. Conventional treatments include corticosteroids, and other immunosuppressants when indicated, and measures to reduce proteinuria and control blood pressure, but the therapeutic response is variable and many patients show progression, highlighting the need for more effective and novel therapeutic approaches. Cyclodextrins (CDs), widely used as drug carriers to enhance solubility, can also mobilize and promote efflux of cholesterol from cells. Preclinical studies show that CDs reduce renal lipid accumulation and ameliorate podocyte injury in experimental models, supporting the idea that CDs could have a dual role as drug carriers and as direct modulators of lipid-related podocyte injury in lipid-associated forms of FSGS. Given the limited direct clinical data in FSGS, in this article we discuss the biological rationale, preclinical evidence, and remaining knowledge gaps for exploring CDs as an innovative therapeutic strategy. Full article

The mechanism of kidney injury associated with apolipoprotein L1 (APOL1) risk variants has remained elusive. Complicating this issue is the broad clinical spectrum of APOL1 kidney disease, which has engendered speculation that this reflects multiple mechanisms of kidney injury. APOL1 kidney disease can be rapid in onset with heavy proteinuria, associated with viral infections and categorized pathologically as collapsing focal segmental glomerulosclerosis. Alternatively, APOL1 kidney disease also may present as an insidious, slowly progressive disease, with less proteinuria but losses in glomerular filtration rate and with varied pathology. In addition to APOL1 kidney disease, APOL1 risk variants are also associated with preeclampsia and other conditions related to placental insufficiency. The outcome of these APOL1-associated pregnancy complications frequently results in prematurity and low birth weight, both of which are known risk factors for hypertension and kidney disease later in life due to reduced nephron endowment. The significance of APOL1 risk variants on pregnancy complications that predispose to kidney disease should not be overlooked as a central mechanism of APOL1 kidney disease, especially the insidious forms, which are difficult to distinguish from the spectrum of kidney disease attributable to prematurity and low birth weight. If low nephron endowment is a causal mechanism behind some forms of APOL1 kidney disease, this may have an impact on clinical trials evaluating drugs directly inhibiting APOL1, since in these instances, ongoing APOL1 expression may not be driving podocyte loss and progressive kidney dysfunction. Full article

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

Idiopathic childhood nephrotic syndrome is a common glomerulopathy comprising proteinuria, hypoalbuminemia, and edema. Podocyte dysfunction is central to this disease process. Extracellular vesicles are released from stressed cells and can represent a molecular snapshot of the parent cell of origin. We previously showed that urinary large extracellular vesicles (LEVs) derived from podocytes are increased in patients with nephrotic syndrome relapse. Here, we investigated the role of mitochondrial DNA (mtDNA) within LEVs both in vitro and in vivo, revealing the novel finding that podocytes release LEVs containing mtDNA, driven by mitochondrial stress. A puromycin aminonucleoside nephrosis rat model showed foot process effacement on electron microscopy and urinary LEVs with significantly increased mtDNA. Prednisolone, which drives remission in nephrotic syndrome in children, attenuated mitochondrial stress and reduced the amount of mtDNA content within LEVs in vitro. Lastly, urinary LEVs from children with nephrotic syndrome also contain mtDNA, and it is the podocyte LEV-fraction which is preferentially enriched. Overall, these data support a potential mechanism of podocyte mitochondrial stress in non-genetic, idiopathic pediatric nephrotic syndrome. Full article

The gut microbiota has emerged as a critical modulator in metabolic diseases, with substantial evidence supporting its role in attenuating diabetes-related nephropathy. Recent investigations demonstrate that strategic manipulation of intestinal microflora offers novel therapeutic avenues for safeguarding renal function against diabetic complications. This investigation sought to determine the nephroprotective potential of Lactobacillus rhamnosus GG (LGG) administration in diabetic nephropathy models. Six experimental cohorts were evaluated: control, probiotic-supplemented control, diabetic, diabetic receiving probiotic therapy, diabetic with antibiotics, and diabetic treated with both antibiotics and probiotics. Diabetic conditions were established via intraperitoneal administration of streptozotocin (50 mg/kg) following overnight fasting, according to validated protocols for experimental diabetes induction. Probiotic therapy (3 × 10⁹ CFU/kg, bi-daily) began one month before diabetes induction and continued throughout the study duration. Glycemic indices were monitored at bi-weekly intervals, inflammatory biomarkers, renal function indices, and urinary albumin excretion. The metabolic profile was evaluated through the determination of HOMA-IR and the computation of metabolic syndrome scores. Microbiome characterization employed 16S rRNA gene sequencing alongside metagenomic shotgun sequencing for comprehensive microbial community mapping. L. rhamnosus GG supplementation substantially augmented microbiome richness and evenness metrics. Principal component analysis revealed distinct clustering of microbial populations between treatment groups. The Prevotella/Bacteroides ratio, an emerging marker of metabolic dysfunction, normalized following probiotic intervention in diabetic subjects. Results: L. rhamnosus GG administration markedly attenuated diabetic progression, achieving glycated hemoglobin reduction of 32% compared to untreated controls. Pro-inflammatory cytokine levels (IL-6, TNF-α) decreased significantly, while anti-inflammatory mediators (IL-10, TGF-β) exhibited enhanced expression. The renal morphometric analysis demonstrated preservation of glomerular architecture and reduced interstitial fibrosis. Additionally, transmission electron microscopy confirmed the maintenance of podocyte foot process integrity in probiotic-treated groups. Conclusions: The administration of Lactobacillus rhamnosus GG demonstrated profound renoprotective efficacy through multifaceted mechanisms, including microbiome reconstitution, metabolic amelioration, and inflammation modulation. Therapeutic effects suggest the potential of a combined probiotic and pharmacological approach to attenuate diabetic-induced renal pathology with enhanced efficacy. Full article

Background: Podocytes are essential for kidney function, and their dysfunction can result in nephrotic syndrome, such as minimal change disease (MCD). Oxidative stress contributes to podocyte damage. We investigated the therapeutic potential of intravenously infused mesenchymal stem cells (MSCs) in a puromycin aminonucleoside (PAN)-induced rodent MCD model, focusing on oxidative stress modulation. Methods: Sprague-Dawley rats were divided into three groups: intact, PAN-Vehicle, and PAN-MSC. MCD was induced through subcutaneous PAN injection. MSCs were infused intravenously in the PAN-MSC group on day 7. Urinary albumin, serum albumin, and creatinine levels were assessed. Histological analysis of the renal cortex was performed. Podocyte protein (NPHS1, NPHS2, and PODXL) and antioxidant enzyme (SOD1, SOD2, and GPX1) levels were measured using quantitative real-time reverse-transcription PCR (qRT-PCR). Results: MSC infusion significantly reduced proteinuria and restored podocyte structure in the PAN-MSC group. Electron microscopy revealed that infused MSCs could inhibit the fusion of the foot process induced by PAN injection. qRT-PCR showed that intravenous infusion of MSCs rescued the inhibition of GPX1 expression. GFP-labeled MSCs accumulated at the podocyte injury sites. Conclusion: Systemic MSC infusion mitigates PAN-induced MCD by reducing proteinuria, preserving podocyte structure, and modulating oxidative stress via the GPX1 pathway, offering a potential therapeutic approach for nephrotic syndrome. Full article

Background/Objectives: Nephrotic syndrome, a glomerular disease caused by podocyte dysfunction, is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Current treatment relies on corticosteroids, which carry the risk of long-term side effects. Physalis angulata has potential as an adjunct therapy for immune-mediated kidney injury. This study aims to evaluate the effects of Physalis angulata extracts on anti-nephrin IgG, IL-4, and podocytopathy through BAFF inhibition in a doxorubicin-induced nephrotic syndrome rat model. Methods: This experimental study involved 36 Sprague–Dawley rats divided into control and treatment groups. The treatment groups received Physalis angulata extract at doses of 500 mg/kgBW, 1500 mg/kgBW, and 2500 mg/kgBW, or in combination with prednisone, alongside a group receiving prednisone monotherapy. Podocytopathy was assessed using proteinuria, nephrin, podocalyxin, and GLEPP-1. Proteinuria was measured using spectrophotometry. Serum BAFF levels, renal IL-4, urinary nephrin, and urinary podocalyxin were analyzed using ELISA. Renal nephrin, renal podocalyxin, GLEPP-1, and BAFF expression were evaluated by immunofluorescence microscopy. The data were analyzed using SPSS 25. Results: The results showed significant reductions in proteinuria, serum BAFF levels, renal BAFF expression, anti-nephrin IgG, IL-4, urinary nephrin, and urinary podocalyxin, along with significant increases in GLEPP-1, renal nephrin, and renal podocalyxin expression, in all treatment groups compared to the nephrotic syndrome control group. The combination of Physalis angulata at 2500 mg/kgBW with prednisone demonstrated the best effects. Conclusions: Physalis angulata shows promise as an adjuvant therapy for nephrotic syndrome by improving podocytopathy through BAFF inhibition. Further research is needed to evaluate its long-term safety, optimize dosing, and explore clinical applications in humans. Full article

Background/Objectives: The pathogenesis of diabetic kidney disease (DKD) is complex and multifactorial. Because of its complications and reduced number of diagnostic biomarkers, it is important to explore new biomarkers with possible roles in the early diagnosis of DKD. Our study aims to investigate the pattern of previously identified metabolites and their association with biomarkers of endothelial dysfunction, proximal tubule (PT) dysfunction, and podocyte injury. Methods: A total of 110 participants, comprising 20 healthy individuals and 90 patients divided in three groups were enrolled in the study: normoalbuminuria, microalbuminuria, and macroalbuminuria. Untargeted and targeted metabolomic methods were employed to assess urinary and serum biomarkers, as well as indicators of endothelial dysfunction, podocyte damage, and PT dysfunction through ELISA techniques. Results: Our research uncovered specific metabolites that exhibit varying levels across different sub-groups. Notably, glycine serves as a distinguishing factor between group C and the normoalbuminuric group. Furthermore, glycine is correlated with endothelial markers, especially VCAM. We observed a gradual decrease in kynurenic acid levels from group C to group P3; this biomarker also demonstrates an inverse relationship with both p-selectin and VCAM. Additionally, tryptophan levels decline progressively from group C to group P3, accompanied by a negative correlation with p-selectin and VCAM. Urinary tiglylglycine also differentiates among the patient groups, with concentrations decreasing as the condition worsens. It shows a strong positive correlation with nephrin, podocalyxin, KIM1, and NAG. Conclusions: In conclusion, glycine, tiglylglycine, kynurenic acid and tryptophan may be considered putative biomarkers for early diagnosis of DKD and T2DM progression. Full article

Fabry disease, the second most common lysosomal storage disorder, is caused by a deficiency of α-galactosidase A (α-Gal A), which leads to an accumulation of glycosphingolipids (GSL), mainly globotriaosylceramide (also known as Gb3). This aberrant GSL metabolism subsequently causes cellular dysfunction; however, the underlying cellular and molecular mechanisms are still unknown. There is growing evidence that damage to organelles, including lysosomes, mitochondria, and plasma membranes, is associated with substrate accumulation. Current methods for the detection of Gb3 are based on anti-Gb3 antibodies, the specificity and sensitivity of which are problematic for glycan detection. This study presents a robust method using lectins, specifically the B-subunit of Shiga toxin (StxB) from Shigella dysenteriae and LecA from Pseudomonas aeruginosa, as alternatives for Gb3 detection in Fabry fibroblasts by flow cytometry and confocal microscopy. StxB and LecA showed superior sensitivity, specificity, and consistency in different cell types compared to all anti-Gb3 antibodies used in this study. In addition, sphingolipid metabolism was analyzed in primary Fabry fibroblasts and α-Gal A knockout podocytes using targeted tandem liquid chromatography-mass spectrometry. Our findings establish lectins as a robust tool for improved diagnostics and research of Fabry disease and provide evidence of SL changes in cultured human cells, filling a knowledge gap. Full article

Diabetic kidney disease (DKD) is a prevalent complication associated with diabetes in which podocyte dysfunction significantly contributes to the development and progression of the condition. Ring finger protein 183 (RNF183) is an ER-localized, transmembrane ring finger protein with classical E3 ligase activity. However, whether RNF183 is involved in glomerular podocyte dysfunction, which is the mechanism of action of DKD, is still poorly understood. In this study, we first demonstrated that RNF183 expression in glomerular podocytes of patients with DKD decreased as the disease progressed. Additionally, our transcriptome sequencing analysis of kidney tissues from diabetic mice revealed a significant reduction in RNF183 expression within the kidney cortex. Similarly, the expression of RNF183 was significantly reduced both in the kidneys of diabetic mice and in human podocytes exposed to high glucose conditions. The downregulation of RNF183 resulted in a suppression of autophagic activity, an increase in apoptotic cell death, and reduced expression of cellular markers in HPC cells. We found that RNF183 was modified via N6-methyladenosine (m6A) RNA methylation. Meanwhile, treatment with meclofenamic acid 2 (MA2), an m6A demethylase inhibitor, resulted in the upregulation of RNF183 expression in HPC cells cultured in high glucose conditions. Furthermore, high glucose treatment decreased the transcription and protein levels in both the m6A writer methyltransferaselike3 (METTL3) and the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). IGF2BP2 assisted with METTL3, which is jointly involved in the transcription of RNF183. Furthermore, we confirmed that RNF183 directly ubiquitinates M2 pyruvate kinase (PKM2) through co-immunoprecipitation (Co-IP) and liquid chromatography–mass spectrometry (LC-MS) experiments. The level of PKM2 ubiquitination was increased following RNF183 overexpression, leading to enhanced PKM2 protein degradation and subsequently alleviating high glucose-induced podocyte damage. The results of this study indicated that RNF183 was regulated via m6A methylation modification and that RNF183 expression was reduced in HPC cells treated with high glucose, which resulted in decreased PKM2 ubiquitination levels and subsequently aggravated podocyte injury. The findings suggest that RNF183 may serve as a potential therapeutic target for diabetic kidney injury, offering new insights into its role in the progression of DKD. Full article

Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1β production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1β production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O₂ production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O₂ production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking. Full article