Abstract Exosomes are extracellular vesicles involved in mediating cell–cell communication by shuttling genetic information and proteins. Here, we investigated whether glomerular endothelial cells-derived exosomes play a central role in mediating podocyte injury and proteinuria formation in diabetic kidney disease and its precise mechanism. In vitro, upon stimulation with high glucose and transforming growth factor-β1, primary human renal glomerular endothelial cells (HRGECs) produced more exosomes that directly mediated podocyte injury. Conversely, pharmacological inhibition of exosome secretion by GW4869, knockdown of tripartite motif-containing 27 (TRIM27) expression, or inhibition of miR-486-5p all abolished the ability of high glucose and transforming growth factor-β1-treated HRGECs to induce podocyte injury. In vivo, injections of HRGEC-derived exosomes aggravated podocyte injury and proteinuria in diabetic mice, which was negated by a miR-486-5p inhibitor. Furthermore, specific knockdown of TRIM27 expression or miR-486-5p in endothelial cells preserved kidney function and attenuated podocyte injury in diabetic mice. Thus, our results suggest that TRIM27-induced glomerular endothelial cell-derived exosomes play a major role in podocyte injury by shuttling miR-486-5p in diabetic kidney disease. Hence, strategies targeting exosomes may be a new direction in developing therapeutics for podocyte injury and proteinuria in diabetic kidney disease.

Renal tubular injury plays a critical role in the progression of lupus nephritis (LN); however, the underlying mechanisms remain poorly understood. In this study, we found that CDO1 expression was significantly positively correlated with the degree of renal tubular injury in renal tissues from LN patients. Using in vitro HK-2 and TCMK-1 cells as well as an in vivo MRL/lpr mouse model, we confirmed that knockdown of CDO1 alleviated renal tubular epithelial cell injury and lipid deposition. Mechanistic studies revealed that CDO1 inhibits lipid metabolism by negatively regulating the expression of ACSM3; notably, downregulation of ACSM3 reversed the ameliorative effects of CDO1 knockdown on lipid deposition and cellular injury. Further investigation demonstrated that ACSM3 deficiency mediates lipid deposition by inducing mitochondrial morphological abnormalities and dysfunction. In summary, this study uncovers a novel mechanism by which the CDO1-ACSM3 axis mediates renal tubular lipid deposition and injury in LN through the regulation of mitochondrial function, offering a potential therapeutic target for this disease.

Tubulointerstitial fibrosis (TIF) represents the final common pathway leading to end-stage renal disease (ESRD) in chronic kidney disease (CKD). Despite fibrosis being well established as a key pathological hallmark, the molecular mediators that drive this process remain incompletely understood. BPI fold-containing family A member 2 (BPIFA2), a secreted innate immune protein of the sPLUNC family, was upregulated in renal tubular epithelial cells across diverse CKD etiologies and strongly correlated with collagen I accumulation and TIF severity. Tubule-specific knockdown of BPIFA2 significantly alleviated renal histopathological injury and fibrosis, whereas exogenous BPIFA2 administration aggravated fibrotic progression. Mechanistically, BPIFA2 promoted epithelial-mesenchymal transition (EMT) in tubular epithelial cells and triggered macrophage-to-myofibroblast transition (MMT) associated with the TGF-β/Smad3 signaling pathway. In conclusion, our findings identify BPIFA2 as a novel profibrotic mediator in CKD. Targeting BPIFA2 or its downstream signaling may offer new therapeutic opportunities for chronic kidney disease.

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN. (c) 2025 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Kidney injury, particularly the processes of inflammation and fibrosis, is a critical pathological feature of Lupus nephritis (LN). BPI fold-containing family A member 2 (BPIFA2), a recently identified parotid gland secretory protein, serves as an early biomarker for acute kidney injury (AKI) and has been shown to promote AKI development. However, the role of BPIFA2 in regulating LN remains largely unclear. In this study, we detected significant BPIFA2 expression in renal tubular epithelial cells of LN patients and animal models, which was strongly correlated with the degree of renal injury. Specifically, targeted knockdown of BPIFA2 in renal tubular epithelial cells significantly alleviated renal tubular injury in LN mice, while its overexpression exacerbated the injury. Mechanistically, under LN conditions, we found that BPIFA2 interacted with low density lipoprotein receptor-related protein 5 (LRP5) in HK-2 cells, resulting in mitochondrial dysfunction and ultimately leading to renal tubular injury. Collectively, our findings not only reveal a novel regulatory mechanism of renal tubular injury in LN but also suggest BPIFA2 as a promising therapeutic target for mitigating LN-associated kidney injury.

Podocytes may mediate local production of Type I interferon (IFN-I), which play a crucial role in the pathogenesis of lupus nephritis (LN). ISGylation is widely involved in the innate immune activation and IFN-I production. Here, we discovered that in patients with LN and pristane-induced model mouse the staining of HERC5, a E3 protein ligase in ISGylation, was markedly elevated in renal glomerulus and associated with podocyte injury. Knockdown of HERC5 in Human podocyte cells significantly decreased the transcription level of Ifn-b1 and subsequently pro-inflammatory factors Tnf-α, Il-6, and Cxcl10, while increasing anti-inflammatory factor Il-10 levels, and reduced podocyte injury induced by LN plasma or IFN-β. Conversely, overexpression of HERC5 reversed the above results, that increased IFN-β generation and excessive activation, and induced podocyte injury. Mechanistically, HERC5 interacts with and facilitates the ISGylation of IRF3, preventing its ubiquitination and subsequent degradation. This interaction stabilizes IRF3, enhancing its activity and leading to sustained IFN-β production and inflammation. In conclusion, our study identifies HERC5 as a key regulator in LN, promoting IRF3 activation and driving sustained IFN-β production and overactivation. This process induces an inflammatory phenotype in podocytes, contributing to their self-injury.

Podocytes may mediate local production of Type I interferon (IFN-I), which play a crucial role in the pathogenesis of lupus nephritis (LN). ISGylation is widely involved in the innate immune activation and IFN-I production. Here, we discovered that in patients with LN and pristane-induced model mouse the staining of HERC5, a E3 protein ligase in ISGylation, was markedly elevated in renal glomerulus and associated with podocyte injury. Knockdown of HERC5 in Human podocyte cells significantly decreased the transcription level of Ifn-b1 and subsequently pro-inflammatory factors Tnf-alpha, Il-6, and Cxcl10, while increasing anti-inflammatory factor Il-10 levels, and reduced podocyte injury induced by LN plasma or IFN-(3. Conversely, overexpression of HERC5 reversed the above results, that increased IFN-(3 generation and excessive activation, and induced podocyte injury. Mechanistically, HERC5 interacts with and facilitates the ISGylation of IRF3, preventing its ubiquitination and subsequent degradation. This interaction stabilizes IRF3, enhancing its activity and leading to sustained IFN-(3 production and inflammation. In conclusion, our study identifies HERC5 as a key regulator in LN, promoting IRF3 activation and driving sustained IFN-(3 production and overactivation. This process induces an inflammatory phenotype in podocytes, contributing to their self-injury.

Tripartite motif-containing 44 (TRIM44), a member of the TRIM protein family, has emerged as a regulator in multiple cancer types, yet its functional role and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly characterized. Here, we identified TRIM44 as a tumor suppressor in ccRCC through integrated clinical and functional analyses. Clinically, TRIM44 expression was significantly downregulated in ccRCC tissues compared with adjacent normal tissues, and its reduced expression correlated with advanced tumor stage and poor patient prognosis. Functionally, gain-of-function and loss-of-function experiments demonstrated that TRIM44 potently inhibited ccRCC cell migration, invasion, and proliferation in vitro and in vivo. Mechanistically, TRIM44 directly interacts with vimentin. Importantly, we found that TRIM44 promotes K48-linked polyubiquitination of vimentin through its B-box domain, thereby targeting vimentin for proteasomal degradation. Collectively, our study establishes TRIM44 as a critical regulator of ccRCC progression through vimentin destabilization, highlighting its potential as both a prognostic biomarker and therapeutic target for ccRCC.

In this paper, a symplectic fission scheme for the association scheme of $ m\times n $ rectangular matrices over the finite field $ \mathbb{F}_q $, denoted by $ {\rm{SMat}}(m\times n, q) $, is constructed, where $ q $ is a power of a prime number. We discuss its association classes and inner automorphism group. In particular, we determine the intersection numbers and automorphism group of $ {\rm{SMat}}(m\times n, q) $ for $ m = 1 $ and $ m = 2 $.

Quadrics are important in finite geometry and can be used to construct binary codes. In this paper, we first define an incidence matrix $ M $ based on points and non-degenerate quadrics in the classical projective space PG$ (n-1, q) $, where $ q $ is a prime power. As a consequence, we establish a binary code $ C(M) $ with the generator matrix $ M $ and determine the dimension of $ C(M) $ when $ q $ and $ n $ are both odd. In particular, we study the minimum distances of $ C(M) $ and $ C^{\perp}(M) $ in PG$ (2, q) $ and give their upper bounds.

Bio-based packaging materials and efficient drug delivery systems have garnered attention in recent years. Among the soluble cellulose derivatives, carboxymethyl cellulose (CMC) stands out as a promising candidate due to its biocompatibility, biodegradability, and wide resources. However, CMC-based films have limited mechanical properties, which hinders their widespread application. This paper aims to address this issue by exploring the molecular interactions between CMC and various additives with different molecular structures, using the rheological method. The additives include O-carboxymethylated chitosan (O-CMCh), N-2-hydroxypropyl-3-trimethylammonium-O-carboxymethyl chitosan (HTCMCh), hydroxypropyltrimethyl ammonium chloride chitosan (HACC), cellulose nanocrystals (CNC), and cellulose nanofibers (CNF). By investigating the rheological properties of film-forming solutions, we aimed to elucidate the influencing mechanisms of the additives on CMC-based films at the molecular level. Various factors affecting rheological properties, such as molecular structure, additive concentration, and temperature, were examined. The results revealed that the interactions between CMC and the additives were dependent on the charge of the additives. Electrostatic interactions were observed for HACC and HTCMCh, while O-CMCh, CNC, and CNF primarily interacted through hydrogen bonds. Based on these rheological properties, several systems were selected to prepare the films, which exhibited excellent transparency, wettability, mechanical properties, biodegradability, and absence of cytotoxicity. The desirable characteristics of these selected films demonstrated the strong biocompatibility between CMC and chitosan and cellulose derivatives. This study offers insights into the preparation of CMC-based food packaging materials with specific properties.

Tubulointerstitial fibrosis (TIF) is an important pathological change that occurs during the development of diabetic kidney disease. The epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is a manifestation of TIF. STAT1, a member of the STAT family of transcription factors, can be modified by the small ubiquitin-related modifier (SUMO), thus affecting the activity of STAT1. The present study investigated the role of STAT1 SUMOylation in high glucose-induced tubular EMT by western blotting, immunocytochemistry, immunofluorescence, co-immunoprecipitation and dual luciferase reporter analysis. The results indicated that in the process of high glucose-induced EMT, STAT1 activation protected the cells from EMT. However, high glucose also increased the SUMOylation of STAT1, which prevented STAT1 from exerting an effective protective role by inhibiting its activity.

Evidences supported many food additives (FAs) possess toxicity to human health due to chronic excessive exposure. Global hygienic standards strictly limit the dosage of each FA and mixture of the same functional FAs. However, the synergetic effects caused by the combination of FAs with different functions require careful evaluation. In the present study, the content of each FA in beverages was determined by HPLC-UV-Vis detec-tion. The cytotoxic effects of selected typical FAs alone or their combination were evaluated in human renal tubular epithelial cells. Mathematical Modeling and bioinformatics methods were employed to evaluate the toxicity of FAs and to predict the key target proteins of FAs on renal tubular cell toxicity, which were verified by western blot. The results indicated above 5 FAs were used in each surveyed beverage. The content of each FA and the respective ratios of the same functional FAs in each beverage did not exceed the maximum permit-ted level. But it was intensively shown that the significant synergistic cytotoxicity for the combination of FAs with lower concentration. The intercellular signaling transduction pathways including JNK/STAT, PI3P/AKT, and MAPK pathways, which could also be activated by PDGF signaling, were predicted to be involved in Fas-induced cytotoxicity. The increased expression of p-STAT3, p-JNK and p-AKT was associated with renal tubular injury. The current study implied the synergistic cytotoxic effect caused by multiple FAs at no toxic dosages via activated cellular transduction pathways regulating cell survival and apoptosis function, which warning of the synergistic toxic effects of different types of FAs.

As one kind of reactive oxygen species, hydrogen peroxide (H2O2) participated in various cellular biological processes including cell differentiation and inflammation responses. Abnormal H2O2 level is closely related to cancer and other diseases. Highly sensitive detection and monitoring H2O2 are of great importance for understanding the roles of H2O2 in cellular dynamic events. Herein, a novel dual stimulus-responsive core-satellite surface-enhanced Raman scattering (SERS) nanoprobe engineered with manganese dioxide (MnO2) and silver nanoparticles (Ag NPs) was constructed for sensitive H2O2 detection. The sensing strategy is based on the target-triggered degradation both of the "core" and "satellite". In this system, the MnO2 core not only could be used as solid supporter to generate "hot spots" that can induce strong SERS signals, but also acted as the responsive unit for H2O2 sensing together with Ag NPs. A good linear relationship in the range from 1 to 100 μM and limit of detection of 7.44 μM were obtained. Moreover, the nanosensor possessed good repeatability. Based on this strategy, the sensitive detection of cellular H2O2 was achieved. Furthermore, the SERS-based H2O2 monitoring during the starvation-induced autophagy was realized by the developed nanoprobes. Our study provides a new way for sensitive H2O2 detection and opens a new avenue for sensing and detection of other biomolecules.

Circular RNAs (circRNAs) are regulators of gene expression that can regulate cell proliferation and programmed cell death and serve as biomarkers in renal diseases. However, the specific traits and underlying mechanisms of circRNAs in the progression of lupus nephritis (LN) have not been elucidated. In the present study, we clarified that hsa_circ_0054595 (circRTN4) was upregulated in human renal mesangial cells (HRMCs). In cultured HRMCs, circRTN4 could enhance FN expression by directly interacting with miR-513a-5p. High circRTN4 expression in monocytes disseminated into HRMCs in an exosomal manner, thereby accelerating cell proliferation and extracellular matrix deposition. In addition, knockdown of circRTN4 in the kidney or peripheral blood alleviated renal damage in MRL/lpr and BALB/c mice. Clinically, high levels of circRTN4 were found in peripheral blood mononuclear cells and kidney tissues of LN patients, hence serving as an effective biomarker for LN detection and a novel therapeutic target. Our findings indicated that circRTN4 exacerbates mesangial cell dysfunction by activating the miR-513a-5p/FN axis in lupus nephritis.

Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule-specific legumain-knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule-specific legumain-knockout mice and the cultured legumain-knockdown HK-2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence-associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain-knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis.

In this paper, we construct a class of association schemes by using pairs of subspaces of vector spaces and determine their full automorphism groups.

目的 探讨STAT1的SUMO4修饰与人近端肾小管上皮细胞(HK-2)表型转化的关系.方法 将HK-2细胞分为空白对照组(NG,5.5 mmol/L葡萄糖)、高糖组(HG,30 mmol/L葡萄糖)、SUMO4-siRNA(转染SUMO4 siRNA)组、NC-siRNA(转染scrimble siRNA)组、UBC9-siRNA(转染UBC9 siRNA)组.采用免疫细胞化学、Western blot法检测E-cadherin、α-SMA、vimentin等的表达;双荧光素酶报告基因分析检测STAT1的转录活性;免疫共沉淀检测STAT1的SUMO4修饰.结果 高糖刺激后,HK-2细胞中E-cadherin表达降低,而vimentin与α-SMA表达增高(P<0.05);高糖上调STAT1的SUMO4修饰;不论是SUMO4 siRNA转染还是UBC9 siRNA转染,均能显著提升STAT1的活性(P<0.01);同时SUMO4 siRNA转染可部分逆转高糖导致的E-cadherin和α-SMA表达变化(P<0.05).结论 抑制STAT1的SUMO4修饰增加STAT1的活性,缓解了高糖诱导的HK-2细胞的上皮-间叶性转化.

Tripartite motif-containing 27 (TRIM27) belongs to the triple motif (TRIM) protein family, which plays a role in a variety of biological activities. Our previous study showed that the TRIM27 protein was highly expressed in the glomerular endothelial cells of patients suffering from lupus nephritis (LN). However, whether TRIM27 is involved in the injury of glomerular endothelial cells in lupus nephritis remains to be clarified. Here, we detected the expression of the TRIM27 protein in glomerular endothelial cells in vivo and in vitro. In addition, the influence of TRIM27 knockdown on endothelial cell damage in MRL/lpr mice and cultured human renal glomerular endothelial cells (HRGECs) was explored. The results revealed that the expression of TRIM27 in endothelial cells was significantly enhanced in vivo and in vitro. Downregulating the expression of TRIM27 inhibited the breakdown of the glycocalyx and the injury of endothelial cells via the FoxO1 pathway. Moreover, HRGECs transfected with the WT-FoxO1 plasmid showed a reduction in impairment caused by LN plasma. Furthermore, suppression of the protein kinase B (Akt) pathway could attenuate damage by mediating the expression of TRIM27. Thus, the present study showed that TRIM27 participated in the injury of glomerular endothelial cells and served as a potential therapeutic target for the treatment of lupus nephritis.

The injury of endothelial cells is one of the initiating factors in restenosis after endovascular treatment. Human urinary kallidinogenase (HUK) is a tissue kallikrein which is used for ischemia-reperfusion injury treatment. Studies have shown that HUK may be a potential therapeutic agent to prevent stenosis after vascular injury, however, the precise mechanisms have not been fully established. This study is to investigate whether HUK can protect endothelial cells after balloon injury or H2O2-induced endothelial cell damage through the proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway. Intimal hyperplasia, a decrease of pinocytotic vesicles and cell apoptosis were found in the common carotid artery balloon injury and H2O2-induced endothelial cell damage, Pyk2/MCU was also up-regulated in such pathological process. HUK could prevent these injuries partially via the bradykinin B2 receptor by inhibiting Pyk2/MCU pathway, which prevented the mitochondrial damage, maintained calcium balance, and eventually inhibited cell apoptosis. Furthermore, MCU expression was not markedly increased if Pyk2 was suppressed by shRNA technique in the H2O2 treatment group, and cell viability was significantly better than H2O2-treated only. In short, our results indicate that the Pyk2/MCU pathway is involved in endothelial injury induced by balloon injury or H2O2-induced endothelial cell damage. HUK plays an protective role by inhibiting the Pyk2/MCU pathway in the endothelial injury.