The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response.
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ABSTRACT:
SUBMITTER: Tang H
PROVIDER: S-EPMC8716832 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-? and PGC-1?. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-? or PGC-1? short interfering RNA. In addition, Rap1b could modulate C/EBP-? binding to the endogenous PGC-1? promoter and the interaction between PGC-1? and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-?-PGC-1? signaling.
| S-EPMC3964498 | biostudies-literature
Project description:BackgroundThis study aimed to investigate whether CXCL1/CXCR2 mediates intestinal injury or white matter injury by delivering inflammatory mediators through the gut-brain regulation axis.MethodsNeonatal SD rats, regardless of sex, were administered 3% dextran sulfate sodium via intragastric administration at different time points to construct necrotizing enterocolitis (NEC) models. Meanwhile, hypoxia and ischemia were induced in 3 day-old SD rats to construct hypoxic-ischemic brain injury (HIBI) and NEC + HIBI models, without gender discrimination. Hematoxylin-eosin staining was used to observe pathological changes in neonatal rat intestinal and brain tissues. Western blotting detected CXCL1 and CXCR2 expression in NEC, HIBI, and NEC + HIBI rat intestinal and brain tissues.ResultsCompared with normal rats, pathological damage to periventricular white matter was observed in the NEC group. In addition to the increased mortality, the histopathological scores also indicated significant increases in brain and intestinal tissue damage in both HIBI and NEC + HIBI rats. Western blotting results suggested that CXCL1 and CXCR2 expression levels were upregulated to varying degrees in the intestinal and brain tissues of NEC, HIBI, and NEC + HIBI neonatal rats compared to that in the normal group. Compared with the HIBI group, the expression of CXCL1 and CXCR2 continued to increase in NEC + HIBI rats at different time points.ConclusionsCXCL1/CXCR2 may be involved in white matter injury in neonatal rats by delivering intestinal inflammatory mediators through the gut-brain axis.
| S-EPMC9675237 | biostudies-literature
Project description:Osteosarcoma, the most common of all bone malignancies, has a high likelihood of lung metastasis. Up until now, the molecular mechanisms involved in osteosarcomas with lung metastases are not clearly understood. Recent observations have shown that the chemokine CXCL1 and its receptor CXCR2 assist with the homing of neutrophils into the tumor microenvironment. Here, we show that the CXCL1/CXCR2 paracrine axis is crucial for lung metastasis in osteosarcoma. In an in vivo lung metastasis model of osteosarcoma, lung blood vessels expressed CXCL1 and osteosarcoma cells expressed the CXCR2 receptor. CXCR2 expression was higher in osteosarcoma cell lines than in normal osteoblast cells. Immunohistochemistry staining of clinical osteosarcoma specimens revealed positive correlations between CXCR2 expression and pathology stage and also vascular cell adhesion molecule 1 (VCAM-1) expression. High levels of CXCL1 secreted by human pulmonary artery endothelial cells (HPAECs) promoted osteosarcoma cell mobility, which was mediated by the upregulation of VCAM-1 expression. When HPAECs-conditioned media was incubated in osteosarcoma cells, we observed that the CXCR2 receptor and FAK/PI3K/Akt/NF-κB signaling cascade were required for VCAM-1 expression. Our findings illustrate a molecular mechanism of lung metastasis in osteosarcoma and indicate that CXCL1/CXCR2 is worth targeting in treatment schemas.
| S-EPMC7072404 | biostudies-literature
Project description:Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and lipid metabolism abnormality serves a key role in the pathogenesis of DN. Sterol regulatory element‑binding protein 1 (SREBP‑1) overexpression mediates aberrant lipid accumulation in renal tubular cells of DN. However, the exact mechanism involved in increased SREBP‑1 has not been fully elucidated. The aim of the present study was to explore the mechanism involved in SREBP‑1 upregulation. Diabetic mice and high glucose‑cultured HKC cells were chosen to detect the expression of FBXW7 and SREBP‑1 using immunohistochemistry, western blotting and PCR. The present study demonstrated that F‑box and WD repeat domain containing 7 (FBXW7) expression was decreased in renal tubular cells of diabetic mice. Moreover, the co‑expression of FBXW7 and SREBP‑1 was observed in renal tubular cells, but not in the glomeruli. High glucose‑induced the downregulation of FBXW7 expression in in vitro cultured HKC cells, which was accompanied by SREBP‑1 upregulation. In addition, overexpression of FBXW7 in HKC cells led to SREBP‑1 downregulation. By contrast, knockdown of FBXW7 caused SREBP‑1 upregulation in HKC cells. It was found that the PI3K/Akt signaling pathway was activated in high glucose‑stimulated HKC cells, and inhibition of PI3K/Akt pathway using LY294002 increased FBXW7 expression and decreased SREBP‑1 expression. Taken together, the present results suggested that FBXW7 mediated high glucose‑induced SREBP‑1 expression in renal tubular cells of DN, under the regulation of the PI3K/Akt signaling pathway.
| S-EPMC7893693 | biostudies-literature
Project description:BackgroundCircular RNA (circRNA) has been shown to mediate diabetic nephropathy (DN) development by regulating renal tubular epithelial cells (RTECs) injury. However, the role and mechanism of circ_0000064 in high glucose (HG)-induced RTECs injury have not been fully elucidated.MethodsHuman RTECs (HK-2) were exposed to HG to induce cell injury. Cell oxidative stress was assessed by detecting the levels of oxidative stress-markers. Moreover, cell proliferation and apoptosis were determined by CCK8 assay, EDU assay and flow cytometry. The protein levels of proliferation markers, apoptosis markers and Rho-associated coiled-coil-containing kinase 1 (ROCK1) were measured using western blot analysis. Furthermore, quantitative real-time PCR was performed to assess the expression of circ_0000064, microRNA (miR)-532-3p and ROCK1. The interaction between miR-532-3p and circ_0000064 or ROCK1 was confirmed by dual-luciferase reporter assay and RNA pull-down assay.ResultsOur results revealed that HG treatment could promote HK-2 cells oxidative stress, apoptosis, fibrosis, and inhibit proliferation. Circ_0000064 expression was increased in the serum of DN patients and HG-induced HK-2 cells, and silenced circ_0000064 could relieve HG-induced HK-2 cells injury. MiR-532-3p could be sponged by circ_0000064, and its overexpression also alleviated HG-induced HK-2 cells injury. Besides, the regulation of circ_0000064 knockdown on HG-induced HK-2 cells injury could be reversed by miR-532-3p inhibitor. Additionally, ROCK1 was a target of miR-532-3p, and its expression was inhibited by circ_0000064 knockdown. The inhibition effect of circ_0000064 knockdown on HG-induced HK-2 cells injury also could be reversed by overexpressing ROCK1.ConclusionIn summary, circ_0000064 knockdown might alleviate HG-induced HK-2 cells injury via regulating the miR-532-3p/ROCK1 axis, which provided a new perspective for DN treatment.
| S-EPMC8922934 | biostudies-literature
Project description:Increased p66Shc expression has been associated with diabetic nephropathy (DN). However, whether p66Shc can serve as a potential biomarker for tubular oxidative injury in DN is unknown. We measured the expression of p66Shc in peripheral blood monocytes (PBMs) and renal biopsy tissues from DN patients and then analysed the relationship between p66Shc expression and the clinical characteristics of patients with DN. Patients were divided into 4 groups (class IIa, class IIb, class III and the control group). qPCR, Western blotting and immunohistochemistry were performed. The results showed that both p66Shc and p-p66Shc expression significantly increased in PBMs and kidney tissues of DN patients. Moreover, Spearman's correlation and multiple regression analyses were carried out. A positive relationship between the p66Shc expression and oxidative stress was found. p66Shc and oxidative stress were significant predictors of the degree of tubular damage. In addition, p66Shc expression was positively correlated with the concentrations of ?-NAG, UACR and 8-OHdG, low-density lipoprotein and blood glucose levels, and duration of diabetes in patients with DN from class IIa to class III. These data indicated that increased expression of p66Shc may serve as a therapeutic target and a novel biomarker of DN.
| S-EPMC4932503 | biostudies-literature
Project description:Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and has become a serious medical issue globally. Although it is known to be associated with glomerular injury, tubular injury has been found to participate in DN in recent years. However, mechanisms of diabetic renal tubular injury remain unclear. Here, we investigated the differentially expressed genes in the renal tubules of patients with DN by analyzing three RNA-seq datasets downloaded from the Gene Expression Omnibus database. Gene set enrichment analysis and weighted gene co-expression network analysis showed that DN is highly correlated with the immune system. The immune-related gene SERPINA3 was screened out with lasso regression and Kaplan-Meier survival analyses. Considering that SERPINA3 is an inhibitor of mast cell chymase, we examined the expression level of SERPINA3 and chymase in human renal tubular biopsies and found that SERPINA3 was upregulated in DN tubules, which is consistent with the results of the differential expression analysis. Besides, the infiltration and degranulation rates of mast cells are augmented in DN. By summarizing the biological function of SERPINA3, chymase, and mast cells in DN based on our results and those of previous studies, we speculated that SERPINA3 is a protective immune-related molecule that prevents renal tubular injury by inhibiting the proliferation and activation of mast cells and downregulating the activity of chymase.
| S-EPMC9592916 | biostudies-literature
Project description:PurposeIt was reported that the chemokine (C-X-C motif) ligand 1 (CXCL1) from cancer cells stimulated the recruitment of bone marrow-derived mesenchymal cells (BM-MCs) into tumor stroma via chemokine (C-X-C motif) receptor 2 (CXCR2) signaling. We conducted this retrospective study to determine the clinicopathologic significance of the CXCL1-CXCR2 axis in human gastric cancer.MethodsThe correlations between the clinicopathological features of 270 primary gastric carcinomas and CXCL1 in cancer cells and CXCR2 in stromal cells were analyzed in immunohistochemical studies. The effect of gastric cancer cells on the expression of CXCR2 in BM-MCs was examined using diffuse-type gastric cancer cell lines in vitro.ResultsThe expression of CXCL1 in cancer cells was correlated with T invasion (T2-T4), lymph node metastasis, lymphatic invasion, venous invasion, peritoneal cytology, peritoneal metastasis and CXCR2 expression in stromal cells. The expression of CXCR2 in stromal cells was correlated with macroscopic type-4 cancers, histological type, T invasion (T2-T4), lymph node metastasis, lymphatic invasion, infiltration, peritoneal cytology, peritoneal metastasis and CD271 expression in stromal cells. The overall survival of patients with CXCL1 and CXCR2-positive cancer was poorer than that of the patients with negative cancer. Both CXCL1 expression in cancer cells and CXCR2 expression in stromal cells were independent prognostic factors for gastric cancer patients.ConclusionThe expressions of CXCL1 in cancer cells and CXCR2 in stromal cells are useful prognostic factors for gastric cancer patients.
| S-EPMC5456266 | biostudies-literature
Project description:The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.
| S-EPMC9218738 | biostudies-literature
Project description:Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.
2024-10-31 | GSE266108 | GEO