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.

Identification of Senescence-Associated Biomarkers in Diabetic Glomerulopathy Using Integrated Bioinformatics Analysis

“…The onset stage of DN was defined as 06 weeks of age, while the early stage of DN was defined as 12 weeks of age. More detailed information about scRNA-seq dataset GSE218563 is seen in https://www.ncbi.nlm.nih.gov/geo/ [ 25 ]. Quality control of cells was implemented based on the previous criteria [ 25 ].…”

Glomerular microcirculation: Implications for diabetes, preeclampsia, and kidney injury

“…In addition, angiotensin II‐induced Ca 2+ transients were markedly inhibited. These data are partially contrasted by Liu et al 69 who performed single‐cell RNA sequencing of renal cells from type 2 diabetic mice to reveal activation of mechanosensitive transcriptional pathway myocardin‐related tissue factor‐serum response factor (MRTF‐SRF) predominantly in mesangial cells. These findings were confirmed in patients with diabetes.…”

Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives

“…180 Since its introduction in 2009, 181 studies based on scRNA-seq are rapidly increasing and have discovered more and more profound information about health and diseases. 182,183 The scRNA-seq technology is also employed by many investigators to characterise cell-type-specific transcriptional heterogeneity in IBD. [184][185][186][187] Besides, a prevailing 'spatial transcriptomics' (ST) has been developed that allows spatially resolved, high-dimensional assessment of gene transcription.…”

“…Single‐cell RNA sequencing (scRNA‐seq) including genomics, transcriptomics, proteomics, epigenomics and metabolomics sequencing, can successfully resolve this problem and directly measure molecular signatures in thousands to millions of individual cells, which provides us an opportunity to uncover the mysteries underlying cellular populations 180 . Since its introduction in 2009, 181 studies based on scRNA‐seq are rapidly increasing and have discovered more and more profound information about health and diseases 182,183 . The scRNA‐seq technology is also employed by many investigators to characterise cell‐type‐specific transcriptional heterogeneity in IBD 184–187 .…”