Disturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF-exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2 + nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN.
BackgroundAcute rejection (AR) in kidney transplantation is an established risk factor that reduces the survival rate of allografts. Despite standard immunosuppression, molecules with regulatory control in the immune pathway of AR can be used as important targets for therapeutic operations to prevent rejection.MethodsWe downloaded the microarray data of 15 AR patients and 37 non-acute rejection (NAR) patients from Gene Expression Omnibus (GEO). Gene network was constructed, and genes were classified into different modules using weighted gene co-expression network analysis (WGCNA). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape were applied for the hub genes in the most related module to AR. Different cell types were explored by xCell online database and single-cell RNA sequencing. We also validated the SLAMF8 and TLR4 levels in Raw264.7 and human kidney tissues of TCMR.ResultsA total of 1,561 differentially expressed genes were filtered. WGCNA was constructed, and genes were classified into 12 modules. Among them, the green module was most closely associated with AR. These genes were significantly enriched in 20 pathway terms, such as cytokine–cytokine receptor interaction, chemokine signaling pathway, and other important regulatory processes. Intersection with GS > 0.4, MM > 0.9, the top 10 MCC values and DEGs in the green module, and six hub genes (DOCK2, NCKAP1L, IL2RG, SLAMF8, CD180, and PTPRE) were identified. Their expression levels were all confirmed to be significantly elevated in AR patients in GEO, Nephroseq, and quantitative real-time PCR (qRT-PCR). Single-cell RNA sequencing showed that AR patient had a higher percentage of native T, CD1C+_B DC, NKT, NK, and monocytes in peripheral blood mononuclear cells (PBMCs). Xcell enrichment scores of 20 cell types were significantly different (p<0.01), mostly immune cells, such as B cells, CD4+ Tem, CD8+ T cells, CD8+ Tcm, macrophages, M1, and monocytes. GSEA suggests that highly expressed six hub genes are correlated with allograft rejection, interferon γ response, interferon α response, and inflammatory response. In addition, SLAMF8 is highly expressed in human kidney tissues of TCMR and in M1 phenotype macrophages of Raw264.7 cell line WGCNA accompanied by high expression of TLR4.ConclusionThis study demonstrates six hub genes and functionally enriched pathways related to AR. SLAMF8 is involved in the M1 macrophages via TLR4, which contributed to AR process.
Background: Renal diabetic changes are frequent in kidney transplantation (KTx) donors. Whether these diabetic changes are reversible remains a topic of debate. This study aimed to test the hypothesized reversibility of diabetic changes after KTx.Methods: C57BL/6J mice were randomly divided into three groups: the control group, early-stage group (ESG), and advanced-stage group (ASG). Diabetes mellitus (DM) was induced in mice by intraperitoneal injection of streptozotocin (STZ) at 50 mg/kg body weight for five consecutive days. Blood glucose levels ≥16.7 mmol/L were indicative of diabetic mice. The kidneys from ESG and ASG were transplanted to control mice 12 or 32 weeks after STZ injection. Kidney tissue, blood, and 24-hour urine specimens of donor and recipient mice were collected before KTx and 28 days after KTx, respectively. We measured the body weight, blood glucose, histological changes, reactive oxygen species (ROS), apoptosis. Electron microscopy was also performed to evaluate the mitochondrial morphology. The expression of NADPH oxidases (NOXs) was assessed by qRT-PCR.Results: Kidneys from early-stage diabetic mice showed evidence of lesion reversal four weeks after KTx, including decreased urinary albumin and reversal of histological changes. Besides, mitochondrial swelling, oxidative stress, apoptosis, and overexpression of NOXs in the kidneys were also suppressed. Conversely, no changes were observed in kidneys from advanced-stage diabetic mice after KTx. Conclusions:We confirmed that early-stage but not advanced-stage diabetic nephropathy (DN) is reversible, which is related to reduced NOX expression and improvement in mitochondrial function. These results indicated that kidneys with early-stage DN could be used for KTx in clinical practice, as the disease may be reversed following KTx.
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