Dataset Information

Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.

ABSTRACT:

Background

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood.

Methods

To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN.

Results

Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration.

Conclusions

Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.

SUBMITTER: Liu S

PROVIDER: S-EPMC9830686 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.

Liu Shuya S Zhao Yu Y Lu Shun S Zhang Tianran T Lindenmeyer Maja T MT Nair Viji V Gies Sydney E SE Wu Guochao G Nelson Robert G RG Czogalla Jan J Aypek Hande H Zielinski Stephanie S Liao Zhouning Z Schaper Melanie M Fermin Damian D Cohen Clemens D CD Delic Denis D Krebs Christian F CF Grahammer Florian F Wiech Thorsten T Kretzler Matthias M Meyer-Schwesinger Catherine C Bonn Stefan S Huber Tobias B TB

Genome medicine 20230110 1

<h4>Background</h4>Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood.<h4>Methods</h4>To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN.<h ...[more]

PMID: 36627643

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Project description:BACKGROUND:Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS:We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS:Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS:These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

Dataset Information

Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.

Background

Methods

Results

Conclusions

Publications

Single-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.

Similar Datasets

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