Analysis of renal protective effects of ARB and SGLT2i at single cell level.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE181382 | GEO | 2021/11/05
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:Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identified SMPDL3b as a modulator of insulin signaling and demonstrated that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.
2019-04-12 | GSE129666 | GEO
Project description:Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS -/- mice receiving renin-angiotensin-aldosterone system (RAAS) blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data-analysis method, SOM or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatics analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers.
2022-07-08 | GSE159059 | GEO
Project description:Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying the development and progression of these complications are unclear. Thus, the goal of the current study was to use system biology approaches to examine DKD and DPN pathogenesis in T1D and T2D mouse models on the same genetic background. We optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background and confirmed both develop DKD and DPN. Transcriptomic data from glomeruli and sciatic nerve tissue from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis followed by functional enrichment. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both DKD and DPN in T1D and T2D mice. The gene-level analysis identified a high degree of concordance in DEGs in both DKD and DPN and across diabetes type, suggesting genetic background influences diabetic complications. These findings offer new insight as the influence of genetic background on DPN in mouse models has not been well defined. Collectively, these findings support the role of inflammation and genetic background in complications of both T1D and T2D.
2023-09-08 | GSE222776 | GEO
Project description:Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.
2023-02-24 | GSE209821 | GEO
Project description:Diabetic kidney disease (DKD), a progressive kidney disease, is a major complication associated with diabetes and has become the leading cause of chronic kidney disease in China. Increasing evidences have demonstrated that lncRNAs play vital roles in kidney diseases, including DKD. To search for new ncRNAs involved in DKD, we performed gene expression profiling in the kidney tissues isolated from DKD patients and non-diabetic renal cancer patients undergoing surgical resection by RNA sequencing. And we identified 65 DEncRNAs (29 upregulated and 36 downregulated in DKD) and 171 DEmRNAs (72 upregulated and 99 downregulated in DKD).This study will provide insights into the prevent and treatment of DKD in the future.
2023-02-22 | GSE199838 | GEO
Project description:Purpose: Our study clarifies the mechanism of Huangqi decoction (HQD) against DKD in diabetic db/db mice. Methods: Eight-week-old male diabetic db/db mice were randomly divided into four groups: Model (1% CMC), HQD-L (0.12 g/kg), HQD-M (0.36 g/kg), and HQD-H (1.08 g/kg) groups. Non-diabetic db/m mice were used as a control group. These mice received HQD treatment for 8 weeks continuously. After 8 weeks of feeding, kidneys were harvested to observe the kidney function, pathological changes, micro-assay study, and the protein expression levels. Results: HQD treatment improved the albumin/creatine ratio (ACR) and 24 h urinary albumin, prevented the pathological phenotypes of increased glomerular volume, widened mesangial areas, the proliferation of mesangial matrix, the disappearance of foot processes, the decreased expression of nephrin and the number of podocytes. The expression profile chips were assessed to reveal the global transcriptional response and predict related functions, diseases and pathways. To verify this, we found that HQD treatment activated the protein expressions of BMP1, BMP7, BMPR2, and active-Rap1 and inhibited Smad1 and phospho-ERK. In addition, HQD could improve lipid deposition in the kidneys of db/db mice. Conclusion: HQD prevents the progression of DKD in db/db mice by regulating the transcription of BMPs and their downstream target genes, inhibiting the phosphorylation of ERK and Smad1 by promoting the binding of Rap1 to GTP and regulating the lipid metabolism dysfunction. These provide a new idea for the treatment of DKD. Overall, HQD had a significant protective effect against DKD. This may be related to the fact that HQD promotes the transcription of BMPs and their downstream target genes by upregulating BMPR-II and regulates the phosphorylation of ERK and Smad by promoting the binding of Rap1 to GTP. In addition, HQD also has a noticeable role in regulating lipid metabolism dysfunction in DKD, which provides a new idea for future research on HQD.
2023-04-25 | GSE225477 | GEO
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: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: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