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Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility

Journal article
Authors H. Qi
G. Casalena
S. Shi
L. Yu
Kerstin Ebefors
Y. Sun
W. Zhang
V. D'Agati
D. Schlondorff
Börje Haraldsson
E. Böttinger
I. Daehn
Published in Diabetes
Volume 66
Issue 3
Pages 763-778
ISSN 0012-1797
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 763-778
Language en
Links dx.doi.org/10.2337/db16-0695
Subject categories Clinical Medicine

Abstract

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKDresistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-Targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1-Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis. © 2017 by the American Diabetes Association.

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