Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis
Ilse Daehn, … , Borje Haraldsson, Erwin P. Bottinger
Ilse Daehn, … , Borje Haraldsson, Erwin P. Bottinger
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1608-1621. https://doi.org/10.1172/JCI71195.
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Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis

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-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β 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.

Authors

Ilse Daehn, Gabriella Casalena, Taoran Zhang, Shaolin Shi, Franz Fenninger, Nicholas Barasch, Liping Yu, Vivette D’Agati, Detlef Schlondorff, Wilhelm Kriz, Borje Haraldsson, Erwin P. Bottinger

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Figure 8

EDN1-mediated endothelial cell mitochondrial oxidative stress and dysfunction are required for podocyte apoptosis induced by TGF-β/SMAD signaling in cell death.

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EDN1-mediated endothelial cell mitochondrial oxidative stress and dysfun...
(A) Percentage of MitoSOX bright fluorescent mGECs after 48 hours transwell coculture with POD cells with or without Dox or Dox in the presence of BQ-123 (1 ng/ml) or mitoTEMPO (5 μg/ml). (B) Percentage apoptotic POD cells after coculture with mGECs in transwell inserts without or with Dox or Dox in the presence of BQ-123 (1 ng/ml) or mitoTEMPO (5 μg/ml) for 48 hours. (C) POD cells treated with Dox were treated directly with EDN1 or cultured with control mGEC SN (Ctl ESN), SN from EDN1-treated mGECs transfected with scrambled siRNA (EDN1 SCR siRNA ESN), or SN from EDN1-treated mGECs transfected with EDNRA siRNA (EDN1 EDNRA siRNA ESN), as indicated. Cocultures performed in 10% FCS. For all histograms, each bar represents n = 3 independent experiments ± SEM. *P < 0.05 versus SN controls, #P < 0.05 versus RPMI controls, ##P < 0.05 versus Dox.