Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells

Kerstin Ebefors,Robert J Wiener,Liping Yu,Evren U Azeloglu,Zhengzi Yi,Fu Jia,Weijia Zhang,Margaret H Baron,John C He,Börje Haraldsson,Ilse Daehn

doi:10.1016/j.kint.2019.05.007

Kerstin Ebefors, Robert J Wiener + Show 9 more

Open Access

https://doi.org/10.1016/j.kint.2019.05.007

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Abstract

Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-β receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.

Highlights

Our findings provide compelling evidence that podocyte activation and pathologic crosstalk with endothelial cells via endothelin-1 results in dysfunction and loss of endothelial surface layer, and this event may underlie early albuminuria in early glomerular disease
glomerular endothelial cells (GECs) transcriptome suggests endothelial surface layer (ESL) loss after podocyte activation We examined the early transcriptome of GECs by crossing PodTgfbr[1] mice with Flk1::H2B-EYFP mice, and these mice allow for detection and isolation of GECs through enhanced yellow fluorescent protein (EYFP) expressed under the control of an Flk[1] promoter.[16]
This study provides evidence for important crosstalk between podocytes and GECs, in which sustained activation of Transforming growth factor-b (TGF-b) signaling in podocytes mediated GEC injury and dysfunction via Edn1-endothelin receptor-A (EdnrA)

Summary

Introduction

Our findings provide compelling evidence that podocyte activation and pathologic crosstalk with endothelial cells via endothelin-1 results in dysfunction and loss of endothelial surface layer (glycocalyx), and this event may underlie early albuminuria in early glomerular disease. K Ebefors et al.: Glomerular cell crosstalk and loss of ESL depletion of adjacent podocytes.[14] A similar stressed endothelial-to-podocyte crosstalk could underlie segmental lesions in diabetic kidney disease (DKD).[15] Here, we provide evidence of early GEC injury and ESL degradation in response to podocyte TGF-bR1 signaling activation. Podocyte-derived Edn[1] interacted with increased GEC EdnrA expression resulting in mitochondrial reactive oxygen species (ROS) and activation of ESL degradation and remodeling pathways Together, these crosstalking events could underlie increase in glomerular permeability to albumin in kidney disease

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