Endothelial mitochondrial oxidative stress determines podocyte depletion in
segmental glomerulosclerosis.
Authors Daehn I, Casalena G, Zhang T, Shi S, Fenninger F, Barasch N, Yu L, D'Agati V,
Schlondorff D, Kriz W, Haraldsson B, Bottinger EP
Submitted By Erwin Bottinger on 5/15/2014
Status Published
Journal The Journal of clinical investigation
Year 2014
Date Published 4/1/2014
Volume : Pages 124 : 1608 - 1621
PubMed Reference 24590287
Abstract Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is
commonly associated with proteinuria and progressive loss of glomerular
function, leading to development of chronic kidney disease (CKD). FSGS is
characterized by podocyte injury and depletion and collapse of glomerular
capillary segments. Progression of FSGS is associated with TGF-ß activation in
podocytes; however, it is not clear how TGF-ß signaling promotes disease. Here,
we determined that podocyte-specific activation of TGF-ß signaling in transgenic
mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated
with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial
oxidative stress and dysfunction in adjacent endothelial cells via paracrine
EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted
podocyte apoptosis, and inhibition of EDNRA or scavenging of
mitochondrial-targeted ROS prevented podocyte loss, albuminuria,
glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between
podocytes and endothelial cells in a coculture system. Biopsies from patients
with FSGS exhibited increased mitochondrial DNA damage, consistent with
EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our
studies indicate that segmental glomerulosclerosis develops as a result of
podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial
dysfunction and suggest that targeting the reciprocal interaction between
podocytes and endothelia may provide opportunities for therapeutic intervention
in FSGS.

Investigators with authorship
Erwin BottingerMount Sinai School of Medicine