Catheter migration and omental wrapping are common causes of catheter malfunction and often result in catheter removal or replacement. Traditional open surgical catheter repositioning requires creation of a new tunnel， and the incidence of catheter migration after repositioning remains as high as it was before surgery. The suture-traction fixed peritoneal dialysis catheter repositioning technique （tunnel-preserving repositioning technique） simultaneously repositions the catheter and secures it to the lower abdominal wall， effectively preventing recurrent catheter migration. In addition， it preserves the original tunnel. This technique is simple， reliable， causes minimal patient discomfort， and carries a low risk of infection. The standardized operative procedure for this suture-traction fixed peritoneal dialysis catheter repositioning technique is summarized below to provide a reference for clinical practitioners.

Cisplatin is widely used in treating solid tumors, but its dose-limiting nephrotoxicity, which manifests as acute kidney injury (AKI), remains a major clinical challenge. The molecular pathways determining proximal tubular epithelial cell (PTEC) susceptibility during cisplatin-induced injury are not fully elucidated. Here, we identify ubiquitin protein ligase E3 component n-recognin 4 (UBR4) as a key regulator of the integrated stress response (ISR), which plays an important role in regulating reactive oxygen species (ROS) accumulation and mitophagy in the kidney. UBR4 expression was markedly upregulated in PTECs of mice with cisplatin-induced AKI. Tubule-specific Ubr4 deficiency exacerbated kidney dysfunction, tubular damage, and cell death. Mechanistically, UBR4 promoted ubiquitination and degradation of the kinase HRI, thereby constraining ISR overactivation and alleviating its inhibitory effect on mitophagy. Consistent with this mechanism, both genetic enhancement of UBR4 and pharmacological inhibition of the ISR with ISRIB significantly mitigated cisplatin-induced nephrotoxicity. Together, our findings uncover a previously unrecognized UBR4-HRI-ISR regulatory axis that serves as an intrinsic protective mechanism in the kidney and highlight UBR4 as a promising therapeutic target for preventing cisplatin-induced tubular injury.

A well-functioning peritoneal dialysis catheter is a prerequisite for the successful performance of peritoneal dialysis. Catheter migration and omental wrapping are common causes of catheter malfunction. The suture-traction fixed peritoneal dialysis catheter placement technique （the Wang peritoneal dialysis catheter technique） secures the intraperitoneal segment of the peritoneal dialysis catheter to the abdominal wall during catheter insertion， thereby fundamentally addressing catheter migration caused by intestinal distension， displacement of the ascending colon， traction by the omentum， and elastic stress between the abdominal wall segment and the intraperitoneal segment of the catheter. For operators who are not yet highly experienced in catheter placement， as long as the intraperitoneal segment of the peritoneal dialysis catheter is reliably fixed， catheter migration can also be effectively reduced. The standardized operative procedure for this suture-traction fixed peritoneal dialysis catheter placement technique is summarized below to provide a reference for clinical practitioners.

Abstract Background Mutations in and functional inactivation of the Gorab gene cause gerodermia osteodysplastica (GO), a disease featuring wrinkled skin and osteoporosis, but the underlying mechanisms of skin aging remain incompletely understood. Methods By crossing the Gorab conditional knockout mouse model (Gorabflox/flox) with Col1a2‐cre/ERT tool mice, pregnant dams at embryonic day 16.5 (E16.5d) and 6‐week‐old offspring were induced with tamoxifen dissolved in a corn oil solution (3 mg/150 μL per mouse) to develop a dermal Gorab knockout mouse model. Then, aging phenotypes were analyzed, and mechanistic studies were performed. Results Conditional knockout of Gorab at two different time points (embryonic and postnatal) resulted in elevated levels of aging‐related proteins (P53, P21, P16) and a reduction in levels of extracellular matrix (ECM) components, including collagen, fibrillin‐1, vimentin, fibronectin, laminin, and versican in the ventral and dorsal skin of adult mice. Postnatal knockout had a relatively more pronounced effect on skin aging‐related changes. Mechanistically, Gorab knockout impaired the ubiquitination and promoted the accumulation of P53 protein, likely through regulating the E3 ligase RCHY1. This was accompanied by increased HDAC2 levels, reduced histone acetylation, and consequent downregulation of skin ECM proteins, outlining a potential pathway for accelerated skin aging. Conclusions This study elucidates that Gorab mutations in the dermis promote skin aging by causing P53 accumulation and disrupting ECM expression via epigenetic regulation. These findings clarify the biological role of Gorab in skin aging and provide a theoretical basis for related mechanistic research and potential preventive strategies.

Radioresistance is a major problem in non-small cell lung carcinoma (NSCLC) treatment. Osthole is a natural coumarin with antitumor effects. This research sought to clarify if Osthole enhances the sensitivity of NSCLC to radiotherapy and to uncover the underlying mechanisms involved. Cell Counting Kit-8 (CCK-8) assay evaluated the impact of Osthole on the viability of BEAS-2B as well as NSCLC cells, and evaluated the combined effect of different Ionizing radiation (IR) doses with Osthole in order to screen for the appropriate treatment concentration. The malignant biology of NSCLC cells was determined using Scratch-wound assay, clone formation, transwell assay and flow cytometry. To evaluate cellular senescence, SA-β-Gal staining was utilized, and the concentrations of senescence-related cytokines were analyzed using ELISA kits. A model of subcutaneous tumors was developed using nude mice, followed by pathological staining to assess cell growth, apoptosis and changes in indicator protein expression. Western blot evaluated the expression levels of Sirt1/NF-κB pathway, apoptosis, cell cycle and cellular senescence related proteins. Osthole at 40 μM showed no notable influence on BEAS-2B cell viability, but could reduce the viability and clone formation ability of NSCLC cells, hindered their migration and invasion, and triggered apoptosis. Co-treatment of Osthole with IR increased the suppressive effect of IR on the malignant biology of NSCLC cells, and also blocked cells in G1 phase and induced senescence-related marker changes. Furthermore, Osthole modulated the Sirt1/NF-κB pathway, and the Sirt1 agonist SRT1720 alleviated Osthole-induced cell senescence-like phenotype and apoptosis. Osthole treatment reduced the volume and mass of tumor tissue, inhibited cell proliferation and promoted apoptosis. Notably, Osthole also modulated Sirt1/NF-κB pathway and induced cell senescence-like phenotype in vivo. Osthole increases the radiosensitivity of NSCLC cells and promotes cell senescence-like phenotype and G1-phase blockade possibly through modulating Sirt1/NF-κB pathway. Osthole enhances the responsiveness of NSCLC cells to radiotherapy, promotes cell senescence-like phenotype and apoptosis possibly via modulating Sirt1/NF-κB pathway, thus effectively inhibits the malignant progression of NSCLC.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, characterized by tubular epithelial cell (TECs) senescence, inflammation, and fibrosis. This study investigates the role of estrogen-related receptor alpha (ERRα) in regulating TECs senescence in DKD through nitric oxide synthase 2 (NOS2)-mediated citrulline metabolism. We demonstrate that ERRα expression is significantly downregulated in renal tubular cells of both diabetic mice and DKD patients, correlating with increased senescence markers and the senescence-associated secretory phenotype (SASP). Mechanistically, transcriptome and chromatin immunoprecipitation sequencing confirmed that ERRα regulates NOS2 transcription. TECs-specific knockout of ERRα led to reduced NOS2 expression and decreased citrulline levels, exacerbating TECs injury and senescence. In contrast, TECs-specific knock-in of ERRα alleviated TECs injury and senescence and restored citrulline metabolism. These findings indicate that ERRα plays a critical role in regulating NOS2-mediated citrulline metabolism, which is essential for maintaining kidney function and mitigating tubular senescence in DKD. Furthermore, overexpression of NOS2 and supplementation with citrulline ameliorated renal dysfunction and cellular senescence in diabetic mice, underscoring the importance of this metabolic axis. Modulating ERRα and NOS2 activity may present a potential therapeutic strategy to reduce kidney injury and slow the progression of DKD.

Diabetic kidney disease is a common chronic complication in patients with diabetes. In clinical practice， the recommended high-protein， low-fat diet for patients with diabetes can effectively control blood glucose and blood lipid levels； however， it may also increase the renal burden， elevate urinary protein excretion， aggravate kidney injury， and promote the onset and progression of diabetic kidney disease. The effects of a high-protein diet on the body， especially on the kidneys， are complex and involve multiple mechanisms and signaling pathways. This review comprehensively summarizes the mechanisms by which a high-protein diet induces kidney injury from the perspectives of renal hemodynamics， renal pathophysiological changes， gut microbiota， advanced glycation end products， sodium-calcium metabolism， purine metabolism， and different protein sources. Even though a high-protein diet is beneficial for glycemic control， patients with diabetes should still avoid high-protein， high-salt diets as much as possible in order to suppress the occurrence and progression of diabetic kidney disease.

Obesity is a global health crisis and a critical risk factor for male infertility, impairing testicular structure and function through hormonal imbalance and oxidative stress. Current therapeutic strategies are often unsatisfactory due to limited efficacy or adverse effects. This study investigated the protective effects and potential molecular mechanisms of Ganoderma lucidum (GL) polysaccharides and triterpenoids against testicular injury in high-fat diet-induced obese male rats. After 12-week GL intervention, reproductive function in obese male rats showed improvement: GL increased litter size, improved sperm motility, reduced sperm DNA fragmentation, and restored serum testosterone, inhibin B, and leptin levels. It also alleviated testicular histopathological damage, downregulated PPT1, and maintained vimentin expression. Notably, GL facilitated delayed fertility recovery and showed a trend toward improved cumulative reproductive success, although fixed-time pregnancy rates were not significantly changed. Mechanistically, GL is associated with enhanced Nrf2 pathway activity, increased SOD1, HO-1, NQO1, and GPX4 levels, and decreased MDA and ROS accumulation, thereby attenuating oxidative stress. It preserved mitochondrial integrity, suppressed germ cell apoptosis (downregulating Bax and caspase-3, upregulating Bcl-2), and promoted cell proliferation. These findings indicate that GL polysaccharides and triterpenoids effectively ameliorate obesity-induced testicular dysfunction, and these beneficial effects are associated with Nrf2-mediated antioxidant responses, mitochondrial homeostasis, apoptosis regulation, and hormonal balance. GL may serve as a promising candidate for obesity-related male infertility.

Percutaneous catheter placement， owing to its advantages of bedside feasibility， procedural independence， and minimal trauma， is theoretically the preferred catheter insertion method for nephrologists. However， blind catheter placement during percutaneous puncture carries the risk of catheter malposition or intestinal perforation， which has greatly hindered its implementation. The suture-traction fixed peritoneal dialysis percutaneous catheter placement technique （modified Seldinger technique） is simpler and faster than conventional percutaneous catheter insertion procedures， causes less surgical trauma， and allows the catheter to be fixed to the lower abdominal wall， thereby effectively preventing catheter migration and omental wrapping. The standardized operative procedure for this suture-traction fixed peritoneal dialysis percutaneous catheter placement technique （modified Seldinger technique） is summarized below to provide a reference for clinical practitioners.

Low nephron endowment constitutes a risk factor for hypertension and renal disease. Epigenetic regulation is crucial for nephron progenitor cell differentiation, affecting nephron number and renal function. The role of many epigenetic modulators, such as Lysine-specific histone demethylase 1a (LSD1 or KDM1A), remains unclear. We used Kdm1a-KO mice to demonstrate that Kdm1a depletion in nephron progenitor cells results in reduced kidney size in neonates and led to glomerulosclerosis, proteinuria, and renal cysts in adults. Notably, Kdm1a deletion in podocytes or tubular cells did not replicate these effects. CRISPR/Cas9-mediated KDM1A deletion in human kidney organoids caused cyst formation and altered gene expression, with snRNA-seq revealing downregulation of podocyte genes and upregulation of metabolic genes. The presence of noncoding RNAs indicated roles in cell proliferation. Our study reveals the critical role of Kdm1a function in nephron development and highlights its affect on transcriptional programming for long-term renal function and susceptibility to cyst formation.

Objective:To systematically evaluate the global research landscape of artificial intelligence (AI) applications in sepsis management to identify evolutionary patterns and inform evidence-based clinical decision-making.Methods:We extracted 1 100 publications from the Web of Science Core Collection (1985-2024), employing Excel, CiteSpace, and VOSviewer for quantitative analysis of national contributions, institutional collaborations, author networks, and keyword evolution.Results:Our findings reveal exponential growth in publication output since 2017 (annual growth rate: 56.3%), driven by advancements in machine learning and interdisciplinary integration. China and the United States emerged as dominant contributors, collectively accounting for over 60% of total publications. The top three institutions were Harvard University, University of California System and Emory University. Keywords co-occurrence and cluster analysis identified research hotspots such as AI-driven prediction models, immune infiltration, precision medicine and single-cell sequencing. Keywords were categorized into five clusters: clinical management of sepsis, pathological mechanism and biomarkers, complications and monitoring, AI-based research, and diagnostic criteria.Conclusions:The publications interest in the application of AI in sepsis management is continuously increasing, especially in aspects such as the immune mechanism of sepsis, critical care management, and treatment plans. Moreover, there is great potential for research in precision medicine and single-cell sequencing. Future research should focus more on the application of AI in the prediction and precise intervention of sepsis.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can cause skeletal muscle, myocardial, and gastrointestinal lesions. However, it is currently unclear whether these lesions are caused directly by viral infection or indirectly after infection and whether there are differences between different animal models. Here, we first compared the pathological changes of skeletal muscle, myocardium, and gastrointestinal smooth muscle of different COVID-19 animal models (rhesus monkey, hamster, ferret, hACE2 transgenic mice, hACE2-K18 transgenic mice, mink, and cat), and analyzed the possible mechanism of pathological changes. Within 5-7 days of being infected with SARS-CoV-2, the three types of muscles in these models were all damaged and inflammatory response to varying degrees, and infiltrating inflammatory cells and factors mainly included CD4T, CD8T cells, macrophages, a small amount of B cells, IL-6, TNF-α, and IFN-γ, and so on. Among them, the pathological changes of the three muscle tissues in the rhesus monkey model were the most significant and closely related to clinical manifestations. It was determined that SARS-CoV-2 can infect these three types of muscles through in situ hybridization and electron microscopy analysis. Therefore, the performance of muscle lesions in each model was not completely consistent and may be related to multiple factors after SARS-CoV-2 infection, including animal species, direct virus invasion, systemic inflammation after infection, and immune status of the body. This study provides a foundation for selecting models to study muscle lesion mechanisms and treatment strategies, highlighting the need for clinical attention to muscle tissue involvement in COVID-19 patients.

Diabetic kidney disease (DKD) is increasingly recognized as a consequence of impaired mitochondrial quality control in renal tubular epithelial cells (TECs). In this study we show that the nuclear receptor ESRRA (estrogen related receptor alpha) transcriptionally activates ATG5 (autophagy related 5) to sustain PINK1 (PTEN induced kinase 1)-dependent mitophagy and preserve tubular homeostasis. ESRRA and ATG5 expression were markedly reduced in human DKD biopsies, and their abundance correlated positively with estimated glomerular filtration rate and inversely with albuminuria. Conditional deletion of Esrra in mouse tubules or CRISPR-Cas9 knockout in primary TECs suppressed mitophagy, exacerbated mitochondrial dysfunction and aggravated tubulointerstitial fibrosis, whereas tubular Esrra re-expression or Atg5 overexpression restored mitophagy and attenuated renal injury. Multi-omics and mechanistic assays identified the natural polyphenol salvianolic acid C (SAC) as a high-affinity ESRRA agonist that binds Asp326, Phe382 and Ala396, stabilizes the receptor and upregulates ATG5. SAC dose-dependently improved proteinuria, renal function, mitochondrial respiration and insulin sensitivity in db/db and high-fat diet-streptozotocin DKD models without overt toxicity. Metabolomic profiling revealed that ESRRA-ATG5-driven mitophagy targets ARG2 (arginase 2) for autophagy-lysosomal degradation, thereby shifting L-arginine flux from urea production toward nitric-oxide synthesis; exogenous L-arginine partly rescued renal injury in Esrra-deficient mice. Collectively, this study uncovers an ESRRA-ATG5 axis that couples selective mitophagy to L-arginine metabolism as a pivotal defense against DKD, and identifies SAC as a first-in-class, naturally derived ESRRA activator with therapeutic potential.Abbreviations: AAV: adeno-associated virus; ACR: albumin:creatinine ratio; ACTA2: actin alpha 2, smooth muscle; AKI: acute kidney injury; ALB: albumin; ARG2: arginase 2; ATG12: autophagy related 12; ATG16L1: autophagy related 16-like 1; ATG5: autophagy related 5; BafA1: bafilomycin A1; BUN: blood urea nitrogen; CETSA: cellular thermal shift assay; ChIP-qPCR: chromatin immunoprecipitation followed by quantitative PCR; ChIP-Seq: chromatin immunoprecipitation sequencing; Co-IP: co-immunoprecipitation; CON: control; Cr: creatinine; DEGs: differentially expressed genes; DHE: dihydroethidium; DKD: diabetic kidney disease; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; ESRRA: estrogen related receptor alpha; FSGS: focal segmental glomerulosclerosis; GSEA: gene set enrichment analysis; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; HG: high glucose; HOMA-IR: homeostatic model assessment of insulin resistance; IF: immunofluorescence; IgAN: immunoglobulin A nephropathy; IHC: immunohistochemistry; IOD: integrated optical density; ITT: insulin tolerance test; KD: equilibrium dissociation constant; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; LUC: luciferase; MCN: minimal change nephrosis; MST: microscale thermophoresis; MTS: mitochondrial targeting sequence; NAFLD: non-alcoholic fatty liver disease; NIH: National Institutes of Health; NO: nitric oxide; OCR: oxygen consumption rate; PAS: periodic acid-Schiff; PCR: polymerase chain reaction; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative PCR; RNA-seq: RNA sequencing; ROS: reactive oxygen species; RT-qPCR: reverse transcription quantitative PCR; SAC: salvianolic acid C; SAFI: salvianolic acid for injection; SDH: succinate dehydrogenase; SEM: standard error of the mean; SPF: specific pathogen-free; SPR: surface plasmon resonance; STZ: streptozotocin; TCA: tricarboxylic acid; TECs: tubular epithelial cells; TEM: transmission electron microscopy; TFAM: transcription factor A, mitochondrial.

Chronic kidney disease (CKD) is a major health issue, with podocyte injury with senescence playing a central role in glomerulosclerosis. This study investigates the link between glycolysis-derived serine metabolism and podocyte injury with senescence, focusing on the role of phosphoglycerate kinase 1 (PGK1) in the regulation of L-serine synthesis and podocyte homeostasis. Using in vivo and in vitro models, we examined the effects of angiotensin II (Ang II)-induced metabolic dysregulation on serine metabolism and its impact on podocyte function. The results demonstrate that Ang II downregulates PGK1 expression through the transcription factor FOXA1, leading to reduced L-serine biosynthesis, mitochondrial dysfunction, and increased cellular senescence in podocytes. Supplementing with L-serine or enhancing PGK1 expression in podocytes alleviated these pathological changes, restored mitochondrial function, and reduced senescence-associated phenotypes in CKD mouse models. Moreover, PGK1 was found to interact with keratin, type II cytoskeletal 1 (KRT1), stabilizing the cytoskeletal integrity of podocytes. These findings identify a novel metabolic pathway linking glycolysis, serine metabolism, and podocyte injury with senescence, suggesting that targeting the PGK1-serine axis may offer therapeutic potential for slowing podocyte senescence and CKD progression.

Background Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear. Methods The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation. Results USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation. Conclusion This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.

Podocytes, highly specialized glomerular epithelial cells, are essential for maintaining the filtration barrier integrity, yet they are particularly susceptible to metabolic stress. Recent advances have identified metabolic reprogramming as a central driver of podocyte injury in diverse glomerular diseases, including diabetic kidney disease and FSGS. Pathologic stimuli, such as hyperglycemia, lipotoxicity, oxidative stress, and inflammatory cytokines, lead to profound alterations in podocyte metabolism, encompassing dysregulation of lipid, glucose, amino acid, and ion handling and activation of immunometabolic pathways. These maladaptive changes result in mitochondrial dysfunction, cytoskeletal disorganization, and inflammatory forms of cell death including pyroptosis and ferroptosis. Mechanistic studies have elucidated the roles of nutrient-sensing pathways (AMP-activated protein kinase, mechanistic target of rapamycin, and sirtuin-1), innate immune sensors (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 and cyclic GMP-AMP synthase-stimulator of IFN genes), and metabolic enzymes (ceramide synthase 6, glutaminase-2, and ornithine decarboxylase-1) in orchestrating this reprogramming. Emerging evidence supports the therapeutic potential of modulating podocyte metabolism, as exemplified by the renoprotective effects of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, and targeted inhibitors of inflammasome or lipid pathways. This review synthesizes recent insights into the structural-metabolic coupling in podocytes, dissects the mechanisms of metabolic derangement in disease contexts, and discusses promising therapeutic strategies aimed at restoring metabolic homeostasis. Understanding the intersection between podocyte metabolism and injury response offers novel avenues for the prevention and treatment of chronic glomerular diseases.

Dermatomyositis is an autoimmune disease. Common treatment with glucocorticoids, immunoglobulins, methotrexate, and rituximab is recommended. Telitacicept is an immunosuppressant that has been approved for the treatment of systemic lupus erythematosus in recent years. Considering the mechanism of action of telitacicept and the pathogenesis of dermatomyositis, it is rational to suppose that telitacicept may be useful in treating dermatomyositis. Here, we describe a case of a 65-year-old male patient with erythema on the face and neck, limb weakness, and edema in both upper and lower limbs. After conventional treatment therapy plus telitacicept, the patient showed significant clinical remission during the maintenance treatment. Methylprednisolone was successfully reduced after injections of telitacicept. After 1 year of follow-up, the patient’s clinical symptoms were improved dramatically. This is the first report indicating that telitacicept is effective for dermatomyositis and it deserves attention.

Key PointsDiabetic kidney disease progression was associated with increased Piezo1 expression in podocytes.Specific Piezo1 deletion alleviated podocyte injury in diabetic models.Piezo1 contributes to podocyte injury through nuclear factor of activated T cell cytoplasmic 1-transient receptor potential cation channel 6 signaling.BackgroundDiabetic kidney disease (DKD) is characterized by progressive injury to glomerular podocytes due to sustained mechanical stress within the glomerulus. Piezo proteins, acting as cellular mechanosensors, play a pivotal role in mechanotransduction by sensing mechanical forces and regulating intracellular ion flux. This study investigates the role of Piezo1 in the progression of DKD and its mechanistic involvement in podocyte injury.MethodsPodocyte-specific Piezo1 knockout mice were generated using the streptozotocin plus high-fat diet model of DKD. In vitro studies included the use of Piezo1 inhibitors to assess calcium influx, podocyte cytoskeletal rearrangement, and apoptosis under stiff matrix conditions. In addition, NF of activated T-cell cytoplasmic 1 (NFATc1) and transient receptor potential cation channel 6 (TRPC6) signaling pathways were explored to establish their role in Piezo1-mediated podocyte injury. Adeno-associated virus TRPC6 was used to overexpress TRPC6 in podocyte-specific Piezo1 knockout mice to assess the in vivo interaction between Piezo1 and TRPC6.ResultsPodocyte-specific deletion of Piezo1 significantly ameliorated the progression of DKD in diabetic mice. Inhibition of Piezo1 reduced calcium influx, cytoskeletal rearrangement, and podocyte apoptosis in vitro. Mechanistically, Piezo1 activation triggered a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx, perpetuating podocyte injury. TRPC6 overexpression in vivo counteracted the protective effects of Piezo1 deletion, confirming the critical role of the Piezo1/NFATc1/TRPC6 axis in DKD progression.ConclusionsPiezo1 plays a key mechanosensory role in podocyte injury during DKD progression by mediating calcium influx and activating the NFATc1/TRPC6 signaling pathway.

Presently, no specific therapies have been recognized for immunoglobulin A nephropathy (IgAN). Mycophenolate mofetil (MMF) has been verified effective for Chinese patients with IgAN. Telitacicept is a full-human TACI-FC fusion preventing B cells maturation and activation, and it has been proven to be beneficial for IgAN in a phase II clinical trial. This study was designed to observe the efficacy and safety of telitacicept plus low-dose MMF for IgAN treatment. This retrospective cohort study included 24 patients with IgAN, and patients were treated with telitacicept plus MMF. The primary outcome was settled as the changing in proteinuria and estimated glomerular filtration rate (eGFR). The subordinate outcome was set as the changing in hematuria. The mean follow-up time was 23 months. The median baseline proteinuria was 2.5 (1.74, 6.58) g/d, and eGFR was 94.97 (56.8, 120.67) mL/min/1.73 m2. There were noteworthy reductions in proteinuria at 3, 6, 9, 12, 15, 18, 21 and 24 months when compared to the baseline levels [1.45 (0.78, 1.8) g/d [p = 0.0122], 0.505 (0.26, 0.99) g/d [p < 0.0001], 0.48 (0.28, 0.76) g/d [p < 0.0001], 0.3 (0.17, 0.85) g/d [p < 0.0001], 0.23 (0.18, 0.575) g/d [p < 0.0001], 0.18 (0.12, 0.325) g/d [p < 0.0001], 0.14 (0.105, 0.22) g/d [p < 0.0001] and 0.14 (0.103, 0.278) g/d [p < 0.0001]]. All patients maintained stable eGFR during follow-up times. Besides, telitacicept plus MMF remarkably alleviated the hematuria. Telitacicept plus MMF treatment led to not only remarkable clinically significant reduction in proteinuria and hematuria, but also stable serum creatinine value of patients with IgAN without adverse side effects.