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LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate DKD in diabetic mice

ABSTRACT: scRNA-seq analysis confirmed that increased LRG1 is limited to GECs in early diabetic kidneys. As anticipated, LRG1 loss significantly attenuated diabetic glomerulopathy including podocyte loss, and improved renal function. scRNA-seq analysis demonstrated that LRG1 loss was sufficient to reverse all significant molecular pathway changes in diabetic mouse GECs, which were also associated with the dampening of TGF-β-induced gene expression. Moreover, LRG1 loss also led to a significant attenuation of TGF-β-mediated gene expression in podocytes and mesangial cells of diabetic mice. These results indicate that increased LRG1 directly potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner to promote DKD, and indirectly via glomerular cross-talk.

ORGANISM(S): Mus musculus

PROVIDER: GSE269534 | GEO | 2024/12/26

REPOSITORIES: GEO

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Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice

Project description:Endothelial dysfunction promotes the pathogenesis of diabetic nephropathy (DN), which is considered to be an early event in disease progression. However, the molecular changes associated with glomerular endothelial cell (GEC) injury in early DN are not well defined. Most gene expression studies have relied on the indirect assessment of GEC injury from isolated glomeruli or renal cortices. Here, we present transcriptomic analysis of isolated GECs, using streptozotocin-induced diabetic wildtype (STZ-WT) and diabetic eNOS-null (STZ-eNOS−/−) mice as models of mild and advanced DN, respectively. GECs of both models in comparison to their respective nondiabetic controls showed significant alterations in the regulation of apoptosis, oxidative stress, and proliferation. The extent of these changes was greater in STZ-eNOS−/− than in STZ-WT GECs. Additionally, genes in STZ-eNOS−/− GECs indicated further dysregulation in angiogenesis and epigenetic regulation. Moreover, a biphasic change in the number of GECs, characterized by an initial increase and subsequent decrease over time, was observed only in STZ-eNOS−/− mice. This is consistent with an early compensatory angiogenic process followed by increased apoptosis, leading to an overall decrease in GEC survival in DN progression. From the genes altered in angiogenesis in STZ-eNOS−/− GECs, we identified potential candidate genes, Lrg1 and Gpr56, whose function may augment diabetes-induced angiogenesis. Thus, our results support a role for GEC in DN by providing direct evidence for alterations of GEC gene expression and molecular pathways. Candidate genes of specific pathways, such as Lrg1 and Gpr56, can be further explored for potential therapeutic targeting to mitigate the initiation and progression of DN.

2018-12-01 | GSE123177 | GEO

Phospho-antibody microarray anayses for control and DG-LRG1 treated HUVEC cells.

Project description:Deglycosylated-leucine-rich α-2-glycoprotein1 (DG-LRG1) as well as LRG1 was discovered to promote angiogenesis under diabetes mellitus condition through TGF-β independent binding to endoglin. To examine the signaling pathways triggered by DG-LRG1, we subjected whole-cell protein lysates of control and DG-LRG1 treated HUVECs to a Phospho Explorer antibody array analysis using commercial antibody array assay kit (Full Moon Biosystems, Inc.). Samples were probed against 1318 site-specific and phospho-specific antibodies with two replicates per antibody printed on a coated glass microscope slide. Phospho Explorer antibody array experiments and analyses were performed as a custom service by E-Biogen (Ebiogen Inc., Seoul, Republic of Korea).

2020-10-25 | GSE160005 | GEO

Single-Cell RNA Sequencing Unveils Lrg1's Role in Cerebral Ischemia‒Reperfusion Injury by Modulating Various Cells

Project description:Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia-reperfusion injury, but its exact mechanism remains unknown. Here, we utilized scRNA-seq to compare the microenvironmental changes in the brains of Lrg1 knockout mice and wild-type mice following MCAO/R, in order to elucidate the role of Lrg1 after MCAO/R.

2023-12-06 | GSE245386 | GEO

AAV-mediated LRG1 overexpression in diabetic mice

Project description:AAV-mediated LRG1 overexpression in diabetic mice

| PRJNA858802 | ENA

AAV-mediated LRG1 overexpression in diabetic mice

Project description:To investigate the effect of LRG1 overexpression on gene expression of eWAT from db/db mice, we transduced 4-week-old db/db mice with AAV8-eGFP or AAV8-LRG1-FL and harvested eWAT at 7 weeks and 10 weeks of age. We then performed gene expression profiling analysis using data obtained from RNA-seq of eWAT from eGFP- and LRG1-overexpressing mice at two time points.

2022-07-18 | GSE208219 | GEO

RNA sequencing of keratinocytes with or without LRG1 addition

Project description:Leucine-rich-alpha-2-glycoprotein1 (LRG1), a highly conserved member of the leucine-rich repeat family of proteins, has been reported to be involved in several tumors. Previous studies showed that it has great importance in epithelial–mesenchymal transition in colorectal cancer and could promote glioma cell lines invasion and migration. Despite the intimate relationships between LRG1 and migration in cancer research, its role in wound repair or re-epithelialization has not been uncovered. So we dicided using keratinocytes to see its transcriptomes changing after LRG1 addition.

2019-11-11 | GSE122527 | GEO

Single-cell profiling of glomerular cells provides a dynamic picture in experimental diabetic kidney disease

Project description:Background: Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited. Methods: To elucidate the glomerular cell–specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)–deficient (eNOS-/-) mice and control eNOS-/- mice. Results: We identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell–specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury. Conclusion: Our findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.

2019-03-08 | GSE127235 | GEO

Upregulation of FGF13 promotes type 2 diabetic nephropathy by modulating glomerular endothelial mitochondrial homeostasis

Project description:Studies of diabetic glomerular injury raise the possibility of developing useful early biomarkers and therapeutic approaches for the treatment of type 2 diabetic nephropathy (T2DN). In this study, it is found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression, and endothelial-specific deletion of Fgf13 potentially alleviates T2DN damage. Fgf13 deficiency restores the expression of Parkin both in the cytosolic, mitochondrial, and nuclear fractions under diabetic conditions, resulting in improved mitochondrial homeostasis and endothelial barrier integrity due to promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn. The effects of Fgf13 deficiency on mitophagy and apoptosis via Parkin-dependent regulation may be distinct and separable events under diabetic conditions. These data show that the bifunctional role of Fgf13 deficiency in promoting mitophagy and inhibiting apoptosis through Parkin can shape mitochondrial homeostasis regulation in GECs and T2DN progression. Acting as a potential biomarker and therapeutic target for prevention and control of T2DN, mechanistically understanding of the biofunction of FGF13 may also be of relevance to the pathogenesis of other FGF13- and Parkin-associated diseases.

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Single-Cell Profiling of Diabetic Nephropathy in a Murine Model Reveals Novel CellChat Signatures, Podocyte-to-Parietal Epithelial Cells Crosstalk

Project description:We used scRNA-seq to confirm the rich cellular interactions between podocytes and glomerular parietal epithelial cells in early diabetic nephropathy and to construct a global view of early diabetic nephropathy.

2024-10-31 | GSE216510 | GEO

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance [liver_RNA-seq]

Project description:Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. This study identified Leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine. The effects of LRG1 deficiency on liver tissue gene expression were tested in current assay.

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