Podocyte-derived endothelin-1 and endothelial cell endothelin A receptors are essential for glomerular injury in mouse models of focal segmental glomerulosclerosis

Introduction Increased endothelin-1 (ET1) and endothelin receptor A (ET A ) signaling have been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Previous studies have suggested that crosstalk between activated podocytes and glomerular endothelial cells (GECs) could contribute to the pathogenesis of FSGS. Methods To examine this, we developed mouse lines with endothelial cell-targeted and conditional deletion of ET A using the CreloxP system ( Scl:Cre-ET A fl/fl ), as well as targeted deletion of ET1 in podocytes ( Nphs2:Cre-ET1 fl/fl ). Results The absence of endothelial ET A in mice was protective in adriamycin-induced glomerular injury, as evidenced by decreased albuminuria and reduced podocyte depletion. RNAseq from ET1-treated mouse glomerular endothelial cells showed activation of cellular signaling pathways and alteration of matrix component deposition programs via ET A . Endothelin-1 expression was detected in glomerular cells in patient biopsy samples and mice with FSGS. Compared to adriamycin-treated mice, podocyte-specific ET1 knockout mice treated with adriamycin had reduced glomerular injury, albuminuria, and podocyte depletion. Furthermore, canonical transforming growth factor (TGF)β signaling mediates ET1 release by podocytes, and Edn1 knockout in podocytes with inducible TGFβ receptor-1 signaling ( Nphs2:Cre-ET1-Nphs1:TgfbrI ) abrogated glomerular injury and albuminuria upon TGFβ receptor-1 activation. Ultrastructural changes and podocyte depletion were completely prevented in these mice, and there was no increase in GEC-associated ET A expression. Mathematical modelling supports rapid bidirectional diffusion of ET1 across the glomerular basement membrane. Conclusions Our studies provide in vivo evidence that crosstalk of podocyte-derived ET1 with activation of GEC ET A contributes to glomerular injury in FSGS.