title: eNOS deficiency predisposes podocytes to injury in diabetes.
abstract: Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS(-/-) mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS(-/-) mice, even though it inhibited glomerular capillary enlargement in both. In eNOS(-/-) mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS(-/-) mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS(-/-) glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.
authors.affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada.
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
authors.forename: Bailey E
authors.initials: BE
authors.lastname: Stead
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: White
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Ian W
authors.initials: IW
authors.lastname: Gibson
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000235:genetics; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012084:Renin-Angiotensin System / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D005947:Glucose