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The locally activated renin-angiotensin system is involved in albumin permeability in glomerular endothelial cells under high glucose conditions

 Jisun Paeng  ;  Jimin Park  ;  Jae Eun Um  ;  Bo Young Nam  ;  Hye-Young Kang  ;  Seonghun Kim  ;  Hyung Jung Oh  ;  Jung Tak Park  ;  Seung Hyeok Han  ;  Dong-Ryeol Ryu  ;  Tae-Hyun Yoo  ;  Shin-Wook Kang 
Journal Title
Issue Date
Albumins/metabolism* ; Angiotensin II/genetics ; Angiotensin II/metabolism ; Angiotensinogen/genetics ; Angiotensinogen/metabolism ; Animals ; Cell Membrane Permeability/drug effects* ; Cells, Cultured ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology* ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism* ; Glucose/pharmacology* ; Humans ; Kidney Glomerulus/drug effects ; Kidney Glomerulus/metabolism* ; Kidney Glomerulus/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1/genetics ; Receptor, Angiotensin, Type 1/metabolism ; Renin-Angiotensin System/drug effects* ; Sweetening Agents/pharmacology
albuminuria ; diabetic nephropathy ; fenestrae ; glomerular endothelial cells ; renin-angiotensin system
BACKGROUND: Although the diabetic milieu per se , hemodynamic changes, oxidative stress and local growth factors such as angiotensin II (AII) are considered to be mediators in the pathogenesis of diabetic nephropathy, the underlying pathways mediating the changes in glomerular endothelial cells (GECs) are not well understood. Therefore, we investigated changes in the renin-angiotensin system (RAS) components in high glucose (HG)-stimulated GECs and the role of the local RAS in morphological and functional changes in GECs under diabetic conditions. METHODS: We stimulated GECs with 5.6 mM glucose or 30 mM glucose with or without an angiotensin II type I receptor blocker (ARB) in vitro and also performed experiments with Sprague-Dawley rats injected with diluent ( n = 16) or streptozotocin [ n = 16, diabetes (DM)]. Eight rats from each group were treated with ARB for 3 months in vivo . Real-time polymerase chain reaction, western blot analysis, enzyme-linked immunosorbent assay and immunofluorescent staining using cultured GECs were performed. The permeability of GECs to macromolecules was assessed by measuring the passage of fluorescein isothiocyanate-labeled bovine serum albumin. Morphological changes were also evaluated by scanning and transmission electron microscopy. RESULTS: There were significant increases in angiotensinogen expression in HG-stimulated GECs along with significant increases in AI and AII levels. Moreover, the expression of heparan sulfate glycosaminoglycans (HS-GAG) assessed by immunofluorescent staining was significantly lower and the permeability to albumin was significantly higher in GECs exposed to HG medium, and ARB treatment significantly abrogated these changes. Upon electron microscopy examination, the mean size of the GEC fenestrae was significantly greater in HG-stimulated GECs and DM rats, and these increases were significantly ameliorated by ARB. CONCLUSIONS: The local RAS within GECs was activated under HG conditions, and this activation may be associated with both an alteration in GEC fenestration and a decrease in HS-GAG, resulting in the development of albuminuria in diabetic nephropathy.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Nam, Bo Young(남보영)
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
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