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

Genome Med. 2023 Jan 10;15(1):2. doi: 10.1186/s13073-022-01145-4.

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.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Diabetic Nephropathies* / genetics
  • Diabetic Nephropathies* / metabolism
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Mice
  • Signal Transduction
  • Transcriptome