We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility.
- Authors
Qi, Haiying; Casalena, Gabriella; Shi, Shaolin; Liping Yu; Ebefors,2, Kerstin; Sun,1, Yezhou; Weijia Zhang,1; D'Agati, Vivette; Schlondorff, Detlef; Haraldsson, Börje; Böttinger, Erwin; Daehn, Ilse; Yu, Liping; Ebefors, Kerstin; Sun, Yezhou; Zhang, Weijia
- 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 DKD-resistant 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.
- Subjects
KIDNEY disease diagnosis; GLOMERULAR filtration rate; ENDOTHELIAL cells; MITOCHONDRIAL membranes; DISEASE susceptibility; DNA metabolism; ALBUMINURIA; ANIMAL experimentation; ANIMALS; ANTIOXIDANTS; CELL receptors; CELLULAR signal transduction; DIABETES; DIABETIC nephropathies; ENDOTHELINS; ENDOTHELIUM; ENZYME-linked immunosorbent assay; EPITHELIAL cells; FLOW cytometry; HIGH performance liquid chromatography; TYPE 1 diabetes; KIDNEY glomerulus; MICE; MITOCHONDRIA; ORGANOPHOSPHORUS compounds; PIPERIDINE; POLYMERASE chain reaction; RESEARCH funding; SCANNING electron microscopy; OXYGEN consumption; DEOXYRIBONUCLEOSIDES; PHARMACODYNAMICS
- Publication
Diabetes, 2017, Vol 66, Issue 3, p763
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0695