Transforming growth factor-beta (TGF-β), a cytokine with near omnipresence, is an integral part of many vital cellular processes across the human body. The family includes three isoforms: Transforming growth factor-beta 1, 2, and 3. These cytokines play a significant role in the fibrosis cascade. Diabetic kidney disease (DKD), a major complication of diabetes, is increasing in prevalence daily, and the classical diagnosis of diabetes is based on the presence of albuminuria. The occurrence of nonalbuminuric DKD has provided new insight into the pathogenesis of this disease. The emphasis on multifactorial pathways involved in developing DKD has highlighted some markers associated with tissue fibrosis. In diabetic nephropathy, TGF-β is significantly involved in its pathology. Its presence in serum and urine means that it could be a diagnostic tool while its regulation provides potential therapeutic targets. Completely blocking TGF-β signaling could reach untargeted regions and cause unanticipated effects. This paper reviews the basic details of TGF-β as a cytokine, its role in DKD, and updates on research carried out to validate its candidacy.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Podocyte injury and death is a key event in DKD progression. Emerging evidence has indicated that crosstalk between unfolded protein response (UPR) and NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an essential role in DKD progression. However, the involvement of these pathways in podocyte injury and death during DKD remains unclear.

Here, we found that inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) branches of the UPR, NLRP3 inflammasome, and apoptosis were activated in podocytes under DKD and high glucose (HG) conditions. In vitro, inducing ER stress by thapsigargin, and IRE1 or PERK overexpression upon HG treatment stimulated NLRP3 inflammasome-mediated pyroptosis and apoptosis, whereas inhibiting IRE1 or PERK suppressed them. Importantly, we discovered that the newly identified NLRP3-binding partner, thioredoxin-interacting protein (TXNIP), upon activation by the transcription factor (TF) PERK/CCAAT-enhancer-binding protein homologous protein (CHOP), served as a link between IRE1 or PERK branches with NLRP3 inflammasome-mediated pyroptosis and apoptosis. TXNIP expression was promoted in podocytes from DKD patients and db/db mice, as well as in HG-exposed conditionally immortalized human podocyte (HPC). In HG-exposed HPC, IRE1 or PERK overexpression upregulated TXNIP expression, while IRE1 or PERK inhibition downregulated it. TXNIP or CHOP silencing both inhibited HG-upregulated TXNIP, further blocking NLRP3 inflammasome-mediated pyroptosis and apoptosis. Furthermore, NLRP3 overexpression aggravated HG-induced pyroptosis and apoptosis, whereas additional TXNIP silencing reversed them without affecting IRE1 or PERK branches.

In conclusion, our results suggested that UPR/NLRP3 inflammasome-mediated pyroptosis/apoptosis pathway was involved in diabetic podocyte injury, and that targeting the CHOP-TXNIP axis may serve as a promising therapeutic target for DKD.

Diabetic kidney disease (DKD) is one of the common microvascular complications of diabetes. The exploration of serum biomarkers holds promise for improving the efficiency and accuracy of early DKD diagnosis. This study aims to investigate the diagnostic value of transforming growth factor-β1 (TGF-β1) and cystatin C (CysC) in DKD patients.

A total of 126 patients with type 2 diabetes mellitus (T2DM) diagnosed at Dongzhimen Hospital, Beijing University of Chinese Medicine, between May 2021 and March 2023 were enrolled. Patients were categorized based on proteinuria levels and estimated glomerular filtration rate (eGFR). Correlation analyses were conducted to examine the relationships between serum TGF-β1, CysC, and clinical parameters. Logistic regression was applied to identify correlation factors for DKD and renal function impairment in T2DM patients. Furthermore, receiver operating characteristic (ROC) curve analysis was performed to assess diagnostic efficacy.

Significant differences in TGF-β1 and CysC levels were observed across groups with varying proteinuria levels. CysC was positively correlated with TGF-β1 (r = 0.640, p < 0.001). TGF-β1 has been associated with proteinuria levels in T2DM patients. Each unit increase in TGF-β1 was associated with a 1.122-fold and 1.470-fold higher odds of the presence of microalbuminuria and proteinuria, respectively, in the normal proteinuria (NP) group. TGF-β1 and CysC showed varying diagnostic performance. TGF-β1 better distinguished microalbuminuria group (MP) from NP, while CysC alone was less effective. T2DM patients with impaired renal function exhibited significantly higher CysC and TGF-β1 levels compared to those with normal renal function. CysC emerged as an associated factor of renal function decline (OR = 2.255, p = 0.008). CysC demonstrated superior diagnostic efficacy compared to TGF-β1 in predicting renal function impairment (AUC = 0.974).

CysC and TGF-β1 can serve as potential biomarkers for assessing renal impairment and proteinuria in T2DM patients. Their combined evaluation demonstrates diagnostic value and clinical application potential.

Tangshenning (TSN) is a traditional Chinese medicinal formula developed on principles of kidney tonification and collateral unblocking. TSN, formulated from Astragalus mongholicus Bunge, Rheum palmatum L., Ligusticum chuanxiong Hort., and Rosa laevigata Michx., has demonstrated significant clinical efficacy in the treatment of diabetic kidney disease (DKD). Our previous studies have suggested that TSN mitigates tubular injury in DKD by inhibiting ferroptosis, however, the precise molecular targets and mechanistic pathways underlying these effects remain to be fully elucidated.

We investigated whether the Sestrin2/AMPK/PGC-1α axis serves as a key pathway mediating TSN's protective effects against tubular injury in DKD.

In vivo, a spontaneous DKD mouse model was developed using KK-Ay mice. In vitro, human tubular epithelial cells (TECs) were used to establish high glucose and ferroptosis models, as well as a Sestrin2 knockdown model for further analysis. Molecular docking was utilized to examine the binding interactions between TSN's key active components and Sestrin2. Colocalization of Sestrin2 and GPX4 was assessed using dual fluorescence staining. Protein expression levels related to the Sestrin2/AMPK/PGC-1α pathway, ferroptosis markers (SLC7A11 and GPX4), and the tubular injury marker KIM-1 were quantified via Western blot analysis. In vivo, DHE staining, TUNEL staining, and ferrous ion content measurement were performed to evaluate ferroptosis levels in renal tissue. In vitro, the BODIPY 581/591 C11 probe and ferrous ion assay were used to assess ferroptosis levels in TECs. MitoSOX staining, JC-1 assay, and ATP level measurements were conducted to evaluate mitochondrial function in TECs.

In vivo, our results demonstrated that TSN improved renal function, alleviated tubular injury, and reduced pathological damage in DKD mice. Furthermore, TSN upregulated the protein expression of the Sestrin2/AMPK/PGC-1α axis and decreased ferroptosis-related markers in the DKD mouse model. Similarly, in vitro, TSN enhanced the expression of the Sestrin2/AMPK/PGC-1α pathway, restored mitochondrial function, and inhibited ferroptosis in TECs under high glucose and ferroptosis-inducing conditions. Additionally, downregulation of Sestrin2 impaired the therapeutic effects of TSN.

TSN alleviates tubular injury in DKD by activating the Sestrin2/AMPK/PGC-1α pathway, restoring mitochondrial function, and inhibiting ferroptosis in TECs.

To investigate the effect and mechanism of Yishen Tongluo formula (, YSTLF) in streptozotocin-induced diabetic kidney disease mice (DKD) mice.

Thirty Institute of Cancer Research mice (specific pathogen free, SPF grade) were divided into five groups (n = 6 per group): control, DKD model, DKD model with YSTLF (4.9 g/kg), DKD model with YSTLF (9.8 g/kg), and DKD model with captopril. DKD was induced through a single intraperitoneal injection of streptozotocin (150 mg/kg). Body weight, fasting blood glucose and urine C-peptide levels were measured to assess metabolic regulation by YSTLF. Renal function was evaluated using indicators of glomerular and tubular health. Liver function was assessed by measuring aspartate aminotransferase and alanine aminotransferase levels. Renal pathological changes were examined using hematoxylin/eosin staining and transmission electron microscopy. Inflammatory and apoptosis-related factors were analyzed through enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis.

In DKD mice, fasting blood glucose, C-peptide, 24-hour urine protein (UP) levels, and renal damage were elevated, accompanied by increased inflammation and apoptosis. YSTLF significantly reduced 24-hour UP and C-peptide levels and improved kidney and liver function in DKD mice. YSTLF also mitigated glomerular hypertrophy, basement membrane thickening, and podocyte foot process effacement. It upregulated the expression of the podocyte marker podocalyxin. Furthermore, YSTLF alleviated inflammation and apoptosis, likely by reducing the overexpression of monocyte chemoattractant protein (MCP-1), Bax, and Caspase-3 in the kidneys of DKD mice.

These findings suggest that YSTLF ameliorates kidney injury by modulating the expression of inflammatory cytokine MCP-1 and the Bax/Caspase-3 apoptosis pathway, providing a potential therapeutic approach for DKD.

Transcriptional intermediary factor 1γ (TIF1γ) is a negative regulator of TGF-β1 signalling and has been associated with patient survival in renal cell carcinoma. However, its role in diabetes mellitus (DM), particularly in diabetic nephropathy (DN), remains unclear. DN is the leading cause of chronic kidney disease (CKD). We investigated the potential role of TIF1γ in mitigating multiple DM-related complications.

Mice were divided into four groups: db/m+, db/db and db/db mice treated with cytomegalovirus- or TGF-TIF1γ plasmids (40 μg/mouse; intraperitoneally weekly for 16 weeks). Renal injury, fibrosis, function and gene expression related to fibrosis and epithelial-mesenchymal transition (EMT) in the kidneys were assessed. Muscle atrophy, regeneration markers, myokine levels and exercise capacity were evaluated. C2C12 cells were exposed to palmitate with or without TIF1γ transfection, and irisin expression and secretion were measured. Muscle-kidney crosstalk was analysed using conditioned media (CM) from TIF1γ-transfected C2C12 cells in palmitate-treated human kidney (HK)-2 cells. Additionally, HK-2 cells were incubated in CM from fibronectin type III domain-containing protein (FNDC)5-knockdown C2C12 cells to confirm irisin-mediated kidney crosstalk by TIF1γ.

TIF1γ treatment in db/db mice resulted in a significant attenuation of renal tubulointerstitial fibrosis (1.5-fold decrease), glomerular injury (1.8-fold improvement), tubular injury (1.6-fold improvement), renal dysfunction (1.7-fold improvement) and a reduction in EMT-related factors (1.8-fold decrease) (p < 0.05). The levels of administered TIF1γ plasmids were higher in skeletal muscle than in renal tissues. TIF1γ expression was significantly elevated in the skeletal muscle of db/db mice treated with TIF1γ plasmids (6.5-fold) (p < 0.05). Mice receiving both plasmids exhibited a 1.8-fold reduction in pathological muscle morphology and atrophy-related gene expression, a 3.0-fold increase in regeneration-related gene expression and a 1.6-fold improvement in muscle function (p < 0.05). Irisin expression increased by 2.1-fold in skeletal muscle and serum (p < 0.05). In TIF1γ-transfected C2C12 cells, irisin secretion was elevated by 1.5-fold (p < 0.05). CM from TIF1γ-transfected C2C12 cells attenuated EMT in palmitate-treated HK-2 cells, compared with medium from nontransfected C2C12 cells (1.9-fold improvement [p < 0.05]). Conversely, FNDC5 knockdown in C2C12 cells accelerated EMT in palmitate-treated HK-2 cells, as evidenced by decreased bone morphogenetic protein-7 (1.6-fold) and increased EMT-related factors (2.1-fold) (p < 0.05), compared with palmitate alone and small interfering RNA control.

Our findings emphasize the potential of TIF1γ as a multitargeted therapeutic agent for DN, mitigating both renal and muscular complications through direct fibrosis inhibition and indirect myokine-mediated inter-organ crosstalk.

METTL3, a key enzyme in N6-methyladenosine (m6A) modification, plays a crucial role in the progression of renal fibrosis, particularly in chronic active renal allograft rejection (CAR). This study explored the mechanisms by which METTL3 promotes renal allograft fibrosis, focusing on its role in the macrophage-to-myofibroblast transition (MMT). Using a comprehensive experimental approach, including TGF-β1-induced MMT cell models, METTL3 conditional knockout (METTL3 KO) mice, and renal biopsy samples from patients with CAR, the study investigates the involvement of METTL3/Smad3 axis in driving MMT and renal fibrosis during the episodes of CAR. We found that elevated m6A modification and METTL3 levels strongly correlated with enhanced MMT and increased fibrotic severity. METTL3 knockout (METTL3 KO) significantly increased the m6A modification of Smad3, decreased Smad3 expression, and inhibited M2-driven MMT. Smad3 knockdown with siRNA (siSmad3) further inhibited M2-driven MMT, while Smad3 overexpression rescued the inhibitory effects of METTL3 silencing, restoring M2-driven MMT and fibrotic tissue damage. Additionally, the METTL3 inhibitor STM2457 effectively reversed M2-driven MMT and alleviated fibrotic tissue damage in CAR. These findings highlight that METTL3 enhances M2-driven MMT in renal fibrosis during CAR by promoting the TGF-β1/Smad3 axis, suggesting that METTL3 is a promising therapeutic target for mitigating renal fibrosis in CAR.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus, characterized by progressive deterioration of renal structure and function, which may eventually lead to end-stage kidney disease (ESKD). The N6-methyladenosine (m6A) methylation, an important modality of RNA modification, involves three classes of key regulators, writers (e.g., METTL3), erasers (e.g., FTO, ALKBH5) and readers (e.g., YTHDF2), which play important roles in DN. Writers are responsible for introducing m6A modifications on RNAs, erasers remove m6A modifications and readers recognize and bind m6A-modified RNAs to regulate RNAs functions, such as mRNA stability, translation and localization. In DN, abnormal m6A modification may promote kidney injury and proteinuria by regulating key pathways involved in multiple processes, including lipid metabolism and inflammatory response, in kidney cells such as podocytes. Therefore, an in-depth study of the role and mechanism of m6A methylation that are regulated by "writers", "erasers" and "readers" in DN is expected to provide new targets and strategies for the prevention and treatment of DN.

Mitophagy serves as a mitochondrial quality control mechanism to maintain the homeostasis of mitochondria and the intracellular environment. Studies have shown that there is a close relationship between mitophagy and apoptosis. Sestrin2 (Sesn2) is a highly conserved class of stress-inducible proteins that play important roles in reducing oxidative stress damage, inflammation, and apoptosis. However, the potential mechanism of how Sesn2 regulates mitophagy and apoptosis in severe acute pancreatitis (SAP) remains unclear. In the study, RAW264.7 (macrophage cell Line) cellular inflammation model established by lipopolysaccharide (LPS) treatment as well as LPS and CAE-induced SAP mouse model (wild-type and Sen2 Knockout mouse) were used. Our study showed that LPS stimulation significantly increased the level of Sesn2 in RAW264.7 cells, Sesn2 increased mitochondrial membrane potential, decreased inflammation levels, mitochondrial superoxide levels and apoptosis, and also promoted monocyte macrophages toward the M2 anti-inflammatory phenotype, suggesting a protective effect of Sesn2 on mitochondria. Further, Sesn2 increased mitophagy and decreased apoptosis via modulating the PINK1-Parkin signaling. Meanwhile, knockout of Sesn2 exacerbated pancreatic, mitochondrial damage and inflammation in a mouse model of SAP. In addition, the protective effect of Sesn2 against SAP was shown to be associated with mitophagy conducted by the PINK1-Parkin pathway via inhibiting apoptosis. These findings reveal that Sesn2 in balancing mitochondrial autophagy and apoptosis by modulating the PINK1-Parkin signaling may present a new therapeutic strategy for the treatment of SAP.

Osteosarcoma (OS) is the most common primary malignant bone neoplasm. Growing researches have highlighted the tumor promoting role of miR-615-3p in various cancers. Notwithstanding, the biological function and underlying mechanisms of miR-615-3p in OS development still unclear.

Quantitative Real-Time PCR analysis (qRT-PCR) and RNA fluorescence in situ hybridization (FISH) staining were performed to measure miR-615-3p expression in OS. CCK-8 assay, colony formation assay and EdU assay were applied to analyze the OS cell proliferation activity. Cell metastasis abilities were evaluated using Transwell assays. Analysis of apoptosis was performed based on flow cytometric detection. The potential mechanisms of miR-615-3p in OS progression were investigated through RNA immunoprecipitation (RIP) assays, dual-luciferase reporter assays, qRT-PCR and western blotting. In vivo experiments, mouse xenograft model was carried out to assess the tumorigenicity of miR-615-3p.

This study demonstrated a significant upregulation of miR-615-3p in OS. In addition, miR-615-3p knockdown suppressed OS proliferation, invasion, metastasis and EMT. Mechanistically, miR-615-3p regulated sestrin 2 (SESN2) expression negatively by targeting its 3'UTR. Moreover, silencing SESN2 facilitated OS progression and activated mTOR pathway. Noteworthy, the anticancer functions of miR-615-3p knockdown were partially recovered by SESN2 silencing. Taken together, the miR-615-3p/SESN2/mTOR pathway is critical for regulating OS progression.

Our results revealed that miR-615-3p modulated mTOR signaling, thus influencing the progression of OS. For OS treatment, molecular strategies that target the miR-615-3p/SESN2/mTOR pathway is promising.

Renal fibrosis (RF) is a pathological process characterized by the excessive accumulation of extracellular matrix (ECM), which triggers a repair cascade in response to stimuli and pathogenic factors, leading to the activation of molecular signaling pathways involved in fibrosis. This article discusses the key cells, molecules, and signaling pathways implicated in the pathogenesis of RF, with a particular focus on tubular epithelial cells (TECs), cellular senescence, ferroptosis, autophagy, epithelial-mesenchymal transition (EMT), and transforming growth factor-β(TGF-β)/Smad signaling. These factors drive the core and regulatory pathways that significantly influence RF. A comprehensive understanding of their roles is essential. Through a literature review, we explore recent advancements in traditional Chinese medicine (TCM) aimed at reducing RF and inhibiting chronic kidney disease (CKD). We summarize, analyze, and elaborate on the important role of Chinese herbs in RF, aiming to provide new directions for their application in prevention and treatment, as well as scientific guidance for clinical practices.

Although clinical strategies for diabetic nephropathy (DN) therapy include stringent blood pressure control through blockade of the renin-angiotensin system and management of hyperglycemia, the condition is still observed to progress relentlessly.

To elucidate the protective effects of rutin on podocytes in db/db mice with integrative approach of network pharmacology and experimental verification.

The study employs network pharmacology to identify common targets between rutin and DN, constructs a potential protein-protein interaction (PPI) network, and conducts Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking is utilized to evaluate the interaction between rutin and protein targets. Additionally, experimental validation is performed using db/db mice and human podocyte cell models.

Rutin has been found to have a significant renoprotective effect, reducing blood glucose, proteinuria, and improving renal function in db/db mice. Rutin's inhibition of Src kinase reduces the phosphorylation levels of EGFR and ERK, which may mitigate podocyte injury. Additionally, rutin exhibits antioxidant properties, capable of lowering the levels of reactive oxygen species (ROS) in kidney tissue and increasing the activity of antioxidant enzymes like superoxide dismutase (SOD). These effects help protect podocytes from oxidative stress, further supporting the potential application of rutin in the treatment of DN.

The inhibition of rutin on Src kinase blocks high glucose-induced EGFR/ERK transactivation and protects podocyte injury in DN, indicating it might serve as a promising therapeutic agent for podocyte-targeted therapies.

Diabetic foot ulcers (DFUs), a prevalent chronic disease caused by various factors, significantly impact patients' quality of life due to prolonged healing times and increased infection risks. Current treatment modalities, including pharmacological, physical, and surgical interventions, often yield limited efficacy and adverse effects, highlighting the urgent need for novel therapeutic strategies. The objective of this research is to create SIKVAV-modified chitosan hydrogels with the intention of improving the process of skin wound healing in diabetic mice. We synthesized the hydrogels and established a diabetic mice model with skin wounding to evaluate its healing effects and underlying mechanisms. The results of our study indicate that the SIKVAV-modified chitosan hydrogels markedly enhance the wound healing process in diabetic mice. This effect may be attributed to several mechanisms, including differentiation of fibroblasts, proliferation of keratinocytes, the promotion of angiogenesis, stimulation of collagen synthesis, upregulation of growth factor expression, and possible involvement of the TGF-β1/Smad3 signaling pathway. This research not only provides a new biomaterial for the treatment of diabetic wounds but also elucidates the related molecular mechanisms involved in wound healing of DFUs, offering valuable insights for future clinical applications.

The role of histone methyltransferase SETDB1 in renal ischemia-reperfusion (I/R) injury has not been explored yet. This study aims to investigate the potential mechanism of SETDB1 in regulating renal I/R injury and its impact on mitochondrial damage and oxidative stress.

The in vivo model of renal I/R in mice and the in vitro model of hypoxia/reoxygenation (H/R) in human renal tubular epithelial cells (HK-2) were constructed to detect the expression of SETDB1. Next, the specific inhibitor (R,R)-59 and knockdown viruses were used to inhibit SETDB1 and verify its effects on mitochondrial damage and oxidative stress. Chromatin immunoprecipitation (ChIP) and coimmunoprecipitation (CoIP) were implemented to explore the in-depth mechanism of SETDB1 regulating renal I/R injury.

The study found that SETDB1 had a regulatory role in mitochondrial damage and oxidative stress during renal I/R injury. Notably, SESN2 was identified as a target of SETDB1, and its expression was under the influence of SETDB1. Besides, SESN2 mediated the regulation of SETDB1 on renal I/R injury. Through deeper mechanistic studies, we uncovered that SETDB1 collaborates with heterochromatin HP1β, facilitating the labeling of H3K9me3 on the SESN2 promoter and impeding SESN2 expression.

The SETDB1/HP1β-SESN2 axis emerges as a potential therapeutic strategy for mitigating renal I/R injury.

Long-term hypoxia is one of the main causes of pulmonary vascular remodeling in pulmonary hypertension (PH) associated with congenital heart disease (CHD) children. Endothelial to mesenchymal transition (EndMT) is an important pathological basis of pulmonary vascular remodeling in PH. We observed that Fibronectin 1 (FN1) had strong protein-protein interactions with both Thrombospondin 1 (THBS1) and Transglutaminase 2 (TGM2) in PH with venous peripheral bloods samples from pediatric patients and healthy children. LungMAP CellCards and heatmaps of human PAEC in PH patients and lung tissues in hypoxia induced PH mice model were used to show that THBS1 and FN1 were significantly elevated. We studied the relationship between THBS1 and FN1 in vivo, by using SUHX-induced PH mice model, and in vitro, by using hypoxia-induced human PAEC. The results showed that hypoxia could result in EndMT and inhibiting THBS1 could reverse EndMT in vivo and in vitro, verifying our transcriptome results. Taken together, our research demonstrated that THBS1 could mediate hypoxia driven EndMT of PH, providing a new insight of research in the pathophysiology of PH.

Monosodium urate (MSU) crystallisation deposited in local tissues and organs induce inflammatory reactions, resulting in diseases such as gout. MSU has been recognized as a common and prevalent pathology in various clinical conditions. In this study, we investigated the role of MSU in the pathogenesis of diabetic kidney disease (DKD). We induced renal injury in diabetic kidney disease mice using streptozotocin (STZ) and assessed renal histopathological damage using Masson's trichrome staining and Collagen III immunofluorescence staining. We measured the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and uric acid (UA) using ELISA. Protein expression levels of NLRP3, p-NF-κB, SHP2, p-STAT3, and p-ERK1/2 were analyzed by Western blot. To further investigate the role of MSU in diabetic kidney disease, we conducted in vitro experiments. In our in vivo experiments, we found that compared to the Model group, there was a significant increase in interstitial fibrosis in the kidneys of mice after treatment with MSU, accompanied by elevated levels of MDA, SOD, and UA. Furthermore, the protein expression of NLRP3, p-NF-NB, SHP2, p-STAT3, and p-ERK1/2 was upregulated. In our subsequent studies on mouse fibroblasts (L929 cells), we discovered that high glucose, MSU, and TGF-β could promote the expression of P22, GP91, NLRP3, NF-κB, p-NF-κB, p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins. Additionally, we found that SHP2 could counteract the upregulation trend induced by MSU on the expression of p-SHP2, p-EGFR, p-STAT3, and Collagen-III proteins, and inhibitors YQ128, NAC, and Cetuximab exhibited similar effects. Furthermore, immunofluorescence results indicated that SHP2 could inhibit the expression of the fibrosis marker α-SMA in L929 cells. These findings suggest that MSU can promote renal fibroblast SHP2 expression, induce oxidative stress, activate the NLRP3/NF-κB pathway, and enhance diabetic kidney disease fibroblast proliferation through the TGFβ/STAT3/ERK1/2 signaling pathway, leading to renal fibrosis.

Cell deaths maintain the normal function of tissues and organs. In pathological conditions, the abnormal activation or disruption of cell death often leads to pathophysiological effects. Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is linked to high mortality and morbidity rates, imposing a substantial burden on global healthcare systems and economies. Loss and detachment of podocytes are key pathological changes in the progression of DKD. This review explores the potential mechanisms of apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and podoptosis in podocytes, focusing on how different cell death modes contribute to the progression of DKD. It recognizes the limitations of current research and presents the latest basic and clinical research studies targeting podocyte death pathways in DKD. Lastly, it focuses on the future of targeting podocyte cell death to treat DKD, with the intention of inspiring further research and the development of therapeutic strategies.

To examine the role and mechanism of thrombospondin-1 (TSP1) in the development of fibrosis in diabetes mellitus-induced erectile dysfunction (DMED).

DMED was induced by intraperitoneal streptozotocin injection. All rats were categorized into three groups: control group (n=8), DMED group (n=8) and DMED+Leu-Ser-Lys-Leu (LSKL) group (n=8). After eight weeks following the induction of diabetes mellitus, the DMED+LSKL group was subjected to intraperitoneal injections of LSKL twice weekly for four weeks. To measure intracavernous pressure (ICP), a 25-gauge needle connected to a PE tube containing heparin was inserted into the corpus cavernosum (CC). Additionally, a needle was inserted into the carotid artery to measure mean arterial pressure (MAP). Sirius red staining and Masson trichrome staining were utilized to assess CC fibrosis. Moreover, high glucose (HG)-induced CC smooth muscle cells (CCSMCs) and CC fibroblasts (CCFs) were treated with or without LSKL. Western blotting and immunofluorescence were utilized to assess the phosphorylation and expression of related proteins.

Compared with those in the control group, the ratio of the maximum ICP to the MAP markedly decreased in the DMED group, as did the ratio of smooth muscle to collagen and the ratio of collagen I to collagen III. These ratios were greater in the DMED+LSKL group than in the DMED group. TSP1 was highly expressed in the CC of DMED rats. In vitro experiments indicated that TSP1 expression significantly increased in the medium of CCSMCs and CCFs cultured in HG media and that the TGF-β pathway was activated in CCSMCs. Collagen IV was overexpressed in CCSMCs, indicating severe fibrosis was severe. Adding LSKL or knocking TSP1 down can prevent the activation of TGF-β signaling, as well as the overexpression of collagen IV in CCSMCs promoted by TSP1 secreted from CCSMCs itself or CCFs.

TSP1 expression is increased in the CC of DMED rats. HG-induced TSP1 secretion via autocrine signaling from CCSMCs and/or paracrine signaling from CCFs to accelerate penile fibrosis. LSKL, an antagonist of TSP1, could improve erectile dysfunction by inhibiting the TGF-β/SMAD pathway.

Myocardial infarction (MI) is a major disease with high morbidity and mortality worldwide. However, existing treatments are far from satisfactory, making the exploration of potent molecular targets more imperative. The E3 ubiquitin ligase RING finger protein 5 (RNF5) has been previously reported to be involved in several diseases by regulating ubiquitination-mediated protein degradation. Nevertheless, few reports have focused on its function in cardiovascular diseases, including MI.

In this study, we established RNF5 knockout mice through precise CRISPR-mediated genome editing and utilized left anterior descending coronary artery ligation in 9-11-week-old male C57BL/6 mice. Subsequently, serum biochemical analysis and histopathological examination of heart tissues were performed. Furthermore, we engineered adenoviruses for modulating RNF5 expression and subjected neonatal rat cardiomyocytes to oxygen-glucose deprivation (OGD) to mimic ischemic conditions, demonstrating the impact of RNF5 manipulation on cellular viability. Gene and protein expression analysis provided insights into the molecular mechanisms. Statistical methods were rigorously employed to assess the significance of experimental findings.

We found RNF5 was downregulated in infarcted heart tissue of mice and NRCMs subjected to OGD treatment. RNF5 knockout in mice resulted in exacerbated heart dysfunction, more severe inflammatory responses, and increased apoptosis after MI surgery. In vitro, RNF5 knockdown exacerbated the OGD-induced decline in cell activity, increased apoptosis, while RNF5 overexpression had the opposite effect. Mechanistically, it was proven that the kinase cascade initiated by apoptosis signal-regulating kinase 1 (ASK1) activation was closely regulated by RNF5 and mediated RNF5's protective function during MI.

We demonstrated the protective effect of RNF5 on myocardial infarction and its function was dependent on inhibiting the activation of ASK1, which adds a new regulatory component to the myocardial infarction associated network and promises to enable new therapeutic strategy.

Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.

Nuclear pore complexes (NPCs) are sophisticated and dynamic protein structures that straddle the nuclear envelope and act as gatekeepers for transporting molecules between the nucleus and the cytoplasm. NPCs comprise up to 30 different proteins known as nucleoporins (NUPs). However, a growing body of research has suggested that NPCs play important roles in gene regulation, viral infections, cancer, mitosis, genetic diseases, kidney diseases, immune system diseases, and degenerative neurological and muscular pathologies.

In this review, we introduce the structure and function of NPCs. Then We described the physiological and pathological effects of each component of NPCs which provide a direction for future clinical applications.

The literatures from PubMed have been reviewed for this article.

This review summarizes current studies on the implications of NPCs in human physiology and pathology, highlighting the mechanistic underpinnings of NPC-associated diseases.

Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2-/- and Sestrin3-/- mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2-/- and Sestrin3-/- mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2-/- and Sestrin3-/- mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.

To investigate how sleeve gastrectomy (SG), a typical operation of bariatric surgery, attenuated symptom, and progression of diabetic kidney disease (DKD).

DKD model was induced by high-fat diet (HFD) combined with streptozocin in Wistar rats. SG was performed, and the group subjected to sham surgery served as control. The animals were euthanized 12 weeks after surgery, followed by sample collection for the subsequent experiment. The HK-2, a renal proximal tubular epithelial cell line derived from human, was utilized to investigate the potential mechanisms.

SG improved metabolic parameters and glucose homeostasis, and could alleviate DKD in terms of renal function indices as well as histological and morphological structures in DM rats, accompanied with a significant reduction in renal tubular injury. Compared with sham group, SG reduced the renal tubular ferroptosis. To further clarify the mechanism involved, in vitro experiments were performed. In the presence of high glucose, renal tubular TGF-β1 secretion was significantly increased in HK-2 cell line, which led to activation of ferroptosis through TGF-β1/Smad3 signaling pathway. Inhibition of TGF-β1 receptor and phosphorylation of Smad3 significantly ameliorated TGF-β1-mediated ferroptosis. In vivo experiments also found that SG improved the hyperglycemic environment, reduced renal TGF-β1 concentrations, and down-regulated the TGF-β1/Smad3 signaling pathway.

With the capacity to lower the glucose, SG could attenuate the ferroptosis by inhibiting TGF-β1/Smad3 signaling pathway in DKD rats, and eventually attenuated DKD.

Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.

Lumbar spinal canal stenosis is primarily caused by ligamentum flavum hypertrophy (LFH), which is a significant pathological factor. Nevertheless, the precise molecular basis for the development of LFH remains uncertain. The current investigation observed a notable increase in thrombospondin-1 (THBS1) expression in LFH through proteomics analysis and single-cell RNA-sequencing analysis of clinical ligamentum flavum specimens. In laboratory experiments, it was demonstrated that THBS1 triggered the activation of Smad3 signaling induced by transforming growth factor β1 (TGFβ1), leading to the subsequent enhancement of COL1A2 and α-SMA, which are fibrosis markers. Furthermore, experiments conducted on a bipedal standing mouse model revealed that THBS1 played a crucial role in the development of LFH. Sestrin2 (SESN2) acted as a stress-responsive protein that suppressed the expression of THBS1, thus averting the progression of fibrosis in ligamentum flavum (LF) cells. To summarize, these results indicate that mechanical overloading causes an increase in THBS1 production, which triggers the TGFβ1/Smad3 signaling pathway and ultimately results in the development of LFH. Targeting the suppression of THBS1 expression may present a novel approach for the treatment of LFH.

Osteosarcoma is a prevalent malignant bone tumor with a poor prognosis. Mothers against decapentaplegic homolog 3 (Smad3) present as a therapeutic target in antitumor treatment, whereas its functions in the osteosarcoma have not been well explored. In the current study, we aimed to investigate the effects of Smad3 in the progression of osteosarcoma. The tumor immune single-cell hub 2 website was used for graph-based visualization of Smad3 status in osteosarcoma single-cell database. Western Blot was applied to detect the expression of Smad3 protein in cell lines. Colony formation and cell counting kit-8 assays were used to evaluate cell proliferation. Transwell and wound healing assays were used to detect the migration and invasion abilities of cells. Cell apoptosis rates and cell cycle changes were explored by using flow cytometry analysis. The xenograft tumor growth model was applied to explore the effect in tumor growth after Smad3 blockage in vivo. Moreover, to confirm the potential mechanism of Smad3's effects on osteosarcoma, bioinformatics analysis was performed in TARGET-Osteosarcoma and GSE19276 databases. Our study found that the Smad3 protein is overexpressed in 143B and U2OS cells, suppressing the expression of Smad3 protein in osteosarcoma cells by Smad3 target inhibitor (E)-SIS3 or lentivirus can inhibit the proliferation, migration, invasion, promote cell apoptosis, arrest cell G1 cycle in osteosarcoma cells in vitro, and suppress tumor growth in vivo. Furthermore, the bioinformatics analysis demonstrated that high expression of Smad3 is closely associated with low immune status in TARGET-Osteosarcoma and GSE19276 databases. Our study suggested that Smad3 could contribute positively to osteosarcoma progression via the regulation of tumor immune microenvironment, and Smad3 may represent as an valuable potential therapeutic target in osteosarcoma therapy.

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic inflammatory disease with poor clinical outcomes and ineffective drug treatment options. Eupatilin is a major component extracted from the traditional herbal medicine Artemisia asiatica Nakai. Notably, it was demonstrated to have an anti-fibrosis effect in endometrial fibrosis, vocal fold, and hepatic fibrosis. Its role and mechanism in IPF remain unclear.

This study used the TGF-β1-induced human embryonic lung fibroblasts (MRC-5) activation, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model. Western blot, immunofluorescence staining, quantitative real time-PCR, hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to evaluate the effects of eupatilin on fibroblast activation, pulmonary fibrosis, and autophagy. The autophagosomes were observed with a transmission electron microscope (TEM). RNA sequencing was used to determine the signaling pathway and key regulator related to autophagy.

Eupatilin significantly decreased the expression of Col1A1, fibronectin, α-SMA, and SQSTM1/p62. In contrast, it increased the expression of LC3B II/I and the number of autophagosomes in TGF-β1 treated MRC-5, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model; it also alleviated bleomycin-induced lung fibrosis. The KEGG pathway mapping displayed that PI3K/Akt and Sestrin2 were associated with the enhanced fibrogenic process. Eupatilin suppressed the phosphorylation of PI3K/Akt/mTOR. Autophagy inhibitor 3-methyladenine (3-MA) and Akt activator SC-79 abrogated the anti-fibrotic effect of eupatilin. Sestrin2 expression was also downregulated in TGF-β1 treated lung fibroblasts and lung tissues of the bleomycin-induced pulmonary fibrosis mice model. Furthermore, eupatilin promoted Sestrin2 expression, and the knockdown of Sestrin2 significantly aggravated the degree of fibrosis, increased the phosphorylation of PI3K/Akt/mTOR, and decreased autophagy.

These findings indicate that eupatilin ameliorates pulmonary fibrosis through Sestrin2/PI3K/Akt/mTOR-dependent autophagy pathway.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as a major contributor to end-stage renal disease. The glomerular filtration barrier, composed of podocytes, endothelial cells, and the glomerular basement membrane, plays a vital role in maintaining renal function. Disruptions in podocyte function, including hypertrophy, shedding, reduced density, and apoptosis, can impair the integrity of the glomerular filtration barrier, resulting in elevated proteinuria, abnormal glomerular filtration rate, and increased creatinine levels. Hence, recent research has increasingly focused on the role of podocyte injury in DN, with a growing emphasis on exploring therapeutic interventions targeting podocyte injury. Studies have revealed that factors such as lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, and impaired autophagy can contribute to podocyte injury. This review aims to summarize the underlying mechanisms of podocyte injury in DN and provide an overview of the current research status regarding experimental drugs targeting podocyte injury in DN. The findings presented herein may offer potential therapeutic targets and strategies for the management of DN associated with podocyte injury.

Diabetes is a global health problem which is accompanied with multi-systemic complications. It is of great significance to elucidate the pathogenesis and to identify novel therapies of diabetes and diabetic complications. Sestrin2, a stress-inducible protein, is primarily involved in cellular responses to various stresses. It plays critical roles in regulating a series of cellular events, such as oxidative stress, mitochondrial function and endoplasmic reticulum stress. Researches investigating the correlations between Sestrin2, diabetes and diabetic complications are increasing in recent years. This review incorporates recent findings, demonstrates the diverse functions and regulating mechanisms of Sestrin2, and discusses the potential roles of Sestrin2 in the pathogenesis of diabetes and diabetic complications, hoping to highlight a promising therapeutic direction.

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.

Diabetic nephropathy is one of the most important microvascular complications of diabetes, which mainly refers to glomerular capillary sclerosis. Podocytes are an important part of glomerular capillaries. Previous clinical and basic studies have shown that fibrosis is the main factor of diabetic nephropathy. This study aimed to assess the protective mechanism of glycyrrhizic acid (GA) on glomerular podocytes induced by high glucose as we hypothesized that GA may have antifibrotic and anti-inflammatory effects on podocytes through regulation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)/sucrose nonfermenting AMPK-related kinase (SNARK) signaling pathway.

SNARK siRNA was used to transfect podocytes. Real-time quantitative polymerase chain reaction and immunofluorescence staining assays were used for molecular and pathological analysis. The expression levels of key pathway proteins (including TGF-β1, α-SMA, SITR1, AMPKα, LKB1, PGC-1α, NF-κB, IL-6, and TNF-α) were verified by Western blotting. The expression of inflammatory factors in podocytes was detected by ELISA.

We demonstrated that GA decreased the expression of podocyte fibrosis signaling pathway-related factors by upregulating the AMPK pathway and its related factors. However, after transfection of podocytes with SNARK siRNA, there was an increased expression of fibrosis-related factors and inflammation-related factors.

GA can protect podocytes and alleviate fibrosis and inflammation induced by high glucose, which is related to the AMPK signaling pathway. Meanwhile, knockdown of SNARK protein can inhibit the AMPK signaling pathway, aggravate fibrosis, and increase inflammation.

Bone marrow-derived mesenchymal stem cells (MSCs) show podocyte-protective effects in chronic kidney disease. Calycosin (CA), a phytoestrogen, is isolated from Astragalus membranaceus with a kidney-tonifying effect. CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion. However, the protective effect and underlying mechanism of CA-pretreated MSCs (MSCsCA) on podocytes in adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) mice remain unclear.

To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.

ADR was used to induce FSGS in mice, and MSCs, CA, or MSCsCA were administered to mice. Their protective effect and possible mechanism of action on podocytes were observed by Western blot, immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction. In vitro, ADR was used to stimulate mouse podocytes (MPC5) to induce injury, and the supernatants from MSC-, CA-, or MSCsCA-treated cells were collected to observe their protective effects on podocytes. Subsequently, the apoptosis of podocytes was detected in vivo and in vitro by Western blot, TUNEL assay, and immunofluorescence. Overexpression of Smad3, which is involved in apoptosis, was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.

CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells. Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells, which was reversed by MSCCA treatment more significantly than by MSCs or CA alone. When Smad3 was overexpressed in MPC5 cells, MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.

MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis. The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.

Nephropathy is the most prevalent microvascular disorder in diabetes mellitus. Oxidative stress and inflammatory cascade provoked by the persistent hyperglycemic milieu play integral roles in the aggravation of renal injury and fibrosis. We explored the impact of biochanin A (BCA), an isoflavonoid, on the inflammatory response, nod-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and fibrosis in diabetic kidneys. A high-fat-diet/streptozotocin (HFD/STZ)-induced experimental model of diabetic nephropathy (DN) was established in Sprague Dawley rats, and in vitro studies were performed in high-glucose-induced renal tubular epithelial (NRK-52E) cells. Persistent hyperglycemia in diabetic rats was manifested by perturbation of renal function, marked histological alterations, and oxidative and inflammatory renal damage. Therapeutic intervention of BCA mitigated histological changes, improved renal function and antioxidant capacity, and suppressed phosphorylation of nuclear factor-kappa B (NF-κB) and nuclear factor-kappa B inhibitor alpha (IκBα) proteins. Our in vitro data reveal excessive superoxide generation, apoptosis, and altered mitochondrial membrane potential in NRK-52E cells that were cultured in a high-glucose (HG) environment were subsided by BCA intervention. Meanwhile, the upregulated expressions of NLRP3 and its associated proteins, the pyroptosis-indicative protein gasdermin-D (GSDMD) in the kidneys, and HG-stimulated NRK-52E cells were significantly ameliorated by BCA treatment. Additionally, BCA blunted transforming growth factor (TGF)-β/Smad signaling and production of collagen I, collagen III, fibronectin, and alfa-smooth muscle actin (α-SMA) in diabetic kidneys. Our results indicate the plausible role of BCA in attenuating DN, presumably through modulation of the apoptotic cascade in renal tubular epithelial cells and the NF-κB/NLRP3 axis.

Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo. The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.