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Comparative RNA-Seq transcriptome analyses of diabetic nerve and kidney disease II

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE222776 | GEO | 2023/09/08

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.

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Comparative RNA-Seq transcriptome analyses of diabetic nerve and kidney disease II

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