dkNET Webinar: Endothelial Cell Fates in Diabetic Kidney Disease—Lessons from the Kidney Precision Medicine Project

*Watch recorded webinar here: https://youtu.be/JElmO_eeh8A

Join dkNET Webinar on Friday, April 25, 2025, 11 am - 12 pm PT

Presenter: Ricardo Melo Ferreira, PhD, Assistant Research Professor of Medicine, Indiana University School of Medicine

Abstract

The Kidney Precision Medicine Project (https://www.kpmp.org/) obtains altruistically donated biopsies of kidney patients with the purpose of understanding and finding new ways to treat chronic kidney disease (CKD) and acute kidney injury (AKI). A plethora of orthogonal molecular interrogation techniques are used with to uncover mechanisms underlying kidney disease. In this work we sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells. 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 TF network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the TF network accelerated the transition from healthy EC-GCs toward a degenerative (injury) 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. The MEF2C, MEF2A, and TRPS1 TF network carefully balances the fate of the EC-GC in DKD. When the TF network is “on” or over-expressed in DKD, EC-GCs may progress to a prEC state, while TF suppression leads to cell death. SGLT2i therapy may restore the balance of MEF2C activity.

The top 3 key questions that the KPMP resource can answer:
1. How the expression of a gene of interest changes across cell types and conditions?
2. How genes, proteins and metabolites are spatially distributed in different samples?
3. Which datasets I can download and use to complement my research?

Dial-in Information: https://uchealth.zoom.us/meeting/register/DxDgWA4LT_a45dHmRfSIhw

Date/Time: Friday, April 25, 2025, 11 am - 12 pm PT

Upcoming webinars schedule: https://dknet.org/about/webinar