title: Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Haiying
authors.initials: H
authors.lastname: Qi
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casalena
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Shi
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Molecular and Clinical Medicine/Nephrology, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ebefors
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Yezhou
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlondorff
authors.affiliation: Department of Molecular and Clinical Medicine/Nephrology, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Börje
authors.initials: B
authors.lastname: Haraldsson
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.|The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Erwin
authors.initials: E
authors.lastname: Böttinger
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY ilse.daehn@mssm.edu.|The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Ilse
authors.initials: I
authors.lastname: Daehn
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000419:Albuminuria; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004272:DNA, Mitochondrial / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004198:Disease Susceptibility; D019332:Endothelin-1 / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D050527:Mesangial Cells / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010101:Oxygen Consumption; D010880:Piperidines / Q000494:pharmacology; D050199:Podocytes / Q000473:pathology / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D019332:Endothelin-1; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D044022:Receptor, Endothelin A; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine