A MEF2C transcription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease.

INTRODUCTION

The maintenance of a healthy epithelial-endothelial juxtaposition requires crosstalk within glomerular cellular niches. Here, we sought to understand the spatially anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD.

METHODS

From 132 human kidney samples, an integrated multiomics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor networks in glomerular capillary endothelial (EC-GC) and mesangial cells. Data were culled from single nucleus RNA, ATAC-sequencing and four orthogonal spatial transcriptomic technologies for correlation with histopathological and clinical trial data.

RESULTS

We identified a cellular niche in diabetic glomeruli enriched in a proliferative endothelial cell subtype (prEC) and altered vascular smooth muscle cells (VSMCs). Cellular communication within this niche maintained pro-angiogenic signaling with loss of anti-angiogenic factors. We identified a transcription factor network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the transcription factor network accelerated the transition from healthy EC-GCs toward a degenerative injured endothelial phenotype, with concomitant disruption of EC-GC and prEC expression patterns. Glomeruli enriched in the prEC niche had histologic evidence of neovascularization. MEF2C activity was increased in diabetic glomeruli with nodular mesangial sclerosis. The gene regulatory network (GRN) of MEF2C was dysregulated in EC-GCs of patients with DKD, but sodium glucose transporter-2 inhibitor (SGLT2i) treatment reversed the MEF2C GRN effects of DKD.

CONCLUSIONS

The MEF2C, MEF2A, and TRPS1 transcription factor network carefully balances the fate of the EC-GC in DKD. When the transcription factor network is "on" or over-expressed in DKD, EC-GCs may progress to a prEC state, while transcription factor suppression leads to cell death. SGLT2i therapy may restore the balance of MEF2C activity.