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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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Research Article Nephrology

Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis

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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 5

TGF-β signaling in podocytes induces EDNRA specifically in endothelial cells.

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TGF-β signaling in podocytes induces EDNRA specifically in endothelial c...
(A) Quantification by RT-PCR of Ednra mRNA in isolated glomeruli of untreated control PodTgfbr1 mice and PodTgfbr1 mice at day 1 to day 14 of Dox diet (n = 3 mice per group; mean ± SEM; *P < 0.05 versus controls). (B) Immunoperoxidase detection of preproendothelin-1 in control untreated PodTgfbr1 mice or mice with Dox treatment for 1 day (original magnification, ×100 [inset]) or (C) 4 days with or without LY364947 (1 mg/kg). Scale bar: 50 μm. (D) Representative double-immunofluorescence detection of endothelial cell marker CD31 (red) and EDNRA (green) in glomeruli of untreated or day 7 Dox-treated PodTgfbr1 mice. (E) Synaptopodin (green) and EDNRA (red) in glomeruli of a day 7 Dox-treated PodTgfbr1 mouse showing no colocalization in podocytes. (F) EDNRA (red) and 8-oxoG (green) in kidney biopsy from a subject diagnosed with FSGS. (G) mRNA expression of Edn1 and Ednra by POD cell line treated with Dox (1 μg/ml) without or with LY364947 (3 μM) for 0, 6, 24, and 48 hours. (H) Quantification by ELISA of EDN1 release in SN by POD cells treated with DOX for 6 to 48 hours without or with LY364947. Colocalization is indicated by arrows in D and F. Mean ± SEM of 3 independent experiments (A, G, and H). *P < 0.05, **P < 0.01 versus untreated controls. Original magnification, ×63 (D and E); ×40 (F).

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