Gene expression profile of mouse diabetic kidney disease (DKD) injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287026 | GEO | 2025/09/11
REPOSITORIES: GEO
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Project description:Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). To identify individual lipids and lipid networks that may be involved in DKD progression, we performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with nondiabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network. Keywords: Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). To identify individual lipids and lipid networks that may be involved in DKD progression, we performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with non-diabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network.
2022-07-08 | GSE141680 | GEO
Project description:Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cell (GEC) injury. We also observed alleviated glomerulopathy and GEC injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GEC pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and high expression of pyroptosis-related proteins. Strengthening the GEC surface charge by oleylamine significantly inhibited NET-induced GEC pyroptosis. These results indicate that NET-induced alterations in GEC charge are associated with GEC pyroptosis in the pathogenesis of DKD and suggest that NETs are a potential therapeutic target for DKD.
2022-09-01 | GSE189875 | GEO
Project description:Angiotensin receptor blockade (ARB) and sodium-glucose co-transporter 2 inhibitor (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renal protective effects remains unclear. Here, we conducted single cell RNA-sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARB, SGLT2i, or both drugs and db/m mice. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARB has more anti-inflammatory and anti-fibrosis effects while SGLT2i affects more mitochondrial function. We also identified a new PT subcluster which was increased in DKD but reversed by treatments.This new subcluster was also confirmed by Immunostaining of mouse and human kidneys with DKD. Together, our study reveal kidney cell-specific gene signatures in response to ARB and SGLT2i and also identified a new PT subcluster which provides new insight into DKD.
2021-11-05 | GSE181382 | GEO
Project description:Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves diabetic podocyte injury in type 1 DKD mice through attenuation of oxidative stress. However, the direct molecular target of puerarin and its underlined mechanisms in DKD remains unknown. In this study, we first confirmed that puerarin also improved DKD in type 2 diabetic mice (db/db). Through RNA-sequencing of isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory, and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability (DARTS) method combined with mass spectrometry analysis we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. Searching Nephroseq datasets revealed that Gnai1 expression increased in the glomeruli of human DKD. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and kidney cortex of mice treated with peurarin. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.
2022-02-15 | GSE196780 | GEO
Project description:Diabetic kidney disease (DKD) is a significant cause of end-stage renal disease (ESRD), markedly increasing the risk of cardiovascular disease and all-cause mortality. Although mesenchymal stem cells (MSCs) have demonstrated potential in mitigating DKD through various pathways, their specific mechanisms remain unclear. In this study, we observed increased Smad2 phosphorylation and ferroptosis in DKD models, which were alleviated by MSC intervention. Dot blot analysis and the EpiQuik M6A RNA Methylation Quantification Kit revealed elevated m6A modification levels in DKD. Bioinformatics analysis, receiver operating characteristic (ROC) curves, and Western blot (WB) assays indicated a correlation between METTL3 expression and changes in m6A modification in DKD. Knockdown of METTL3 and Smad2 reduced m6A modification and ferroptosis levels. Furthermore, knockdown of METTL3 reversed the increase in m6A modification caused by Smad2 overexpression. Notably, transcriptome and m6A-seq analysis identified S1pr1 as a target gene. Using the GEPIA database, we found a close association between S1pr1 expression and both Smad2 and METTL3 in kidney tissues. The SRAMP tool predicted nine m6A modification sites on S1pr1 mRNA, eight with over 95% credibility and one at position 688 with over 90% credibility. Knockdown of S1pr1 reversed the protective effect of METTL3 knockdown against ferroptosis in DKD, increasing Fe2+, ROS, and ACSL4 levels while decreasing GPX4 and SLC7A11 expression. Finally, MSC intervention and shRNA-mediated METTL3 knockdown increased the reduced S1pr1 levels in DKD kidney tissue. Our findings suggest that upon nuclear translocation, Smad2 promotes S1pr1 gene m6A modification by binding to METTL3, thereby affecting S1pr1 expression and positively regulating cellular ferroptosis in DKD models. MSC intervention can reduce this process, further elucidating the mechanism by which MSCs regulate podocyte ferroptosis in DKD.
2025-09-01 | GSE285781 | GEO
Project description:We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples. Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. Stringent statistical analysis using the Benjamini_Hochberg corrected 2-tailed t-test was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. This Series includes DKD and control glomeruli samples.
2011-08-02 | E-GEOD-30528 | biostudies-arrayexpress
Project description:We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples. Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. Stringent statistical analysis using the Benjamini_Hochberg corrected 2-tailed t-test was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. This Series includes DKD and control tubuli samples.
2011-08-02 | E-GEOD-30529 | biostudies-arrayexpress
Project description:Background: Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated. Methods: In the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD. Results: We found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. Conclusions: NR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.
2023-08-02 | PXD029745 | Pride
Project description:In order to find out the different expression of miRNA in DKD patients and controls, the kidney tissues of DKD and controls were used to do the miRNA mircroassy.
2024-06-30 | GSE179171 | GEO
Project description:Diabetic kidney disease, a major microvascular complication of diabetes, is the primary cause of end-stage renal disease globally 1. Current treatments mainly target glycemic, blood pressure, and lipid control but often fail to prevent renal impairment. Early DKD is characterized by tubular damage, glomerular hypertrophy, thickening of the glomerular basement membrane, and loss of podocytes. Podocyte damage and loss are potentially significant in the pathogenesis of DKD. Hyperglycemia, a critical factor in podocyte injury, can contribute to the progression of DKD. Therefore, mitigating podocyte injury may be a crucial factor in the future management and alleviation of DKD. Chronic hyperglycemia leads to podocyte dysfunction through inflammation, oxidative stress, autophagy, and apoptosis. As is well known, the non-enzymatic glycation of proteins, leading to the formation of advanced glycation end-products (AGEs), constitutes a significant contributing factor to DKD. Notably, recent studies underscore the crucial role of O-linked-N-acetylglucosamine (O-GlcNAc) modification (also known as O-GlcNAcylation) in DKD progression. The hexosamine biosynthesis pathway (HBP) converts glucose to UDP-N -acetylglucosamine (UDP-GlcNAc), a substrate for O-GlcNAcylation, which is catalyzed by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Aberrant O-GlcNAcylation is linked to renal fibrosis, inflammation, and apoptosis, which worsen diabetic kidney function. Elevated levels of O-GlcNAcylation have been observed in renal tissues of diabetic patients, indicating a potential link between hyperglycemia and dysregulated O-GlcNAc signaling. However, the exact molecular mechanisms of O-GlcNAcylation in DKD are not well understood. This study explores the changes in protein and glycosylated protein in podocytes after OGT knockdown to learn the molecular mechanisms of podocyte injury induced by high glucose (HG). A total of 128 up-regulated proteins and 45 down-regulated proteins in OGT knockdown group than in the control group were identified. Furthermore, 55 significantly changed glycosylation modification sites on 43 proteins were identified. To the best of our knowledge, this is the first study to conduct a global analysis of O-GlcNAcylation in podocytes.
2025-02-08 | MSV000097081 | MassIVE