title: 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.forename: Ilse
authors.initials: I
authors.lastname: Daehn
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casalena
authors.forename: Taoran
authors.initials: T
authors.lastname: Zhang
authors.forename: Shaolin
authors.initials: S
authors.lastname: Shi
authors.forename: Franz
authors.initials: F
authors.lastname: Fenninger
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barasch
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlondorff
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kriz
authors.forename: Borje
authors.initials: B
authors.lastname: Haraldsson
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I