biostudies-literatureLiu SEuropean Research CouncilNIDDK NIH HHSUniversitätsklinikum Hamburg-Eppendorf (UKE)2https://www.ebi.ac.uk/biostudies/studies/S-EPMC9830686biostudies-literatureUnknown15(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.<h4>Results</h4>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.<h4>Conclusions</h4>Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.Genome medicineSingle-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.PMC9830686616891P30 DK020572P30 DK081943Lindenmeyer MTLiao ZCohen CDHuber TBFermin DWiech TNelson RGKrebs CFZielinski SGies SELiu SWu GSchaper MDelic DZhao YAypek HBonn SNair VZhang TMeyer-Schwesinger CGrahammer FKretzler MLu SCzogalla JfalseSingle-cell transcriptomics reveals a mechanosensitive injury signaling pathway in early diabetic nephropathy.<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.<h4>Results</h4>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.<h4>Conclusions</h4>Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.2023-01-01T00:00:00Z2023 Jan2024-11-14T12:05:48.796Z2024-11-14T12:05:48.796ZS-EPMC98306863662764310.1186/s13073-022-01145-4