Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice.
Animals
Diabetes Complications
/ etiology
Diabetes Mellitus, Experimental
/ complications
Diabetic Nephropathies
/ etiology
Glomerular Mesangium
/ metabolism
Hypoxia
/ physiopathology
Male
Mice
Mice, Inbred Strains
Nitric Oxide Synthase Type III
/ metabolism
Podocytes
/ metabolism
Transforming Growth Factor beta1
/ metabolism
Vascular Endothelial Growth Factor A
/ metabolism
chronic hypoxia
db/db mice
diabetic glomerulosclerosis
mesangiolysis
podocalyxin
Journal
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
ISSN: 1460-2385
Titre abrégé: Nephrol Dial Transplant
Pays: England
ID NLM: 8706402
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
01
09
2019
accepted:
14
03
2020
pubmed:
1
7
2020
medline:
1
1
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
Chronic hypoxia may play a pivotal role in the development of diabetic nephropathy (DN). However, the precise mechanisms underlying progressive hypoxia-induced glomerular injury remain unclear. We housed db/db mice in a hypoxia chamber (12% O2) for up to 16 weeks beginning at 8 weeks of age. Various urine, serum and kidney abnormalities and glomerular messenger RNA (mRNA) expression were compared with those in age-matched db/db mice housed under normoxia. Levels of urinary albumin and podocalyxin (PCX) were significantly higher in hypoxic mice early during hypoxia. Ultracentrifugation of urine samples revealed that podocytes in the hypoxic mice shed PCX-positive microparticles into the urine. After 16 weeks of hypoxia, the mice also had higher hematocrits with lower serum glucose and various degrees of mesangiolytic glomerulosclerosis with microaneurysms and the infrequent occurrence of nodular lesions. Immunohistologically, hypoxic mice showed significantly decreased endothelial cell densities early during hypoxia and decreased podocyte densities later. In both hypoxic and normoxic mice, glomerular macrophage and transforming growth factor-β1 (TGF-β1) staining significantly increased with aging, without changes in vascular endothelial growth factor or endothelial nitric oxide synthase (eNOS). Glomerular mRNA expression of monocyte chemoattractant protein-1, eNOS and TGF-β1 was significantly enhanced in the hypoxic mice. These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.
Sections du résumé
BACKGROUND
Chronic hypoxia may play a pivotal role in the development of diabetic nephropathy (DN). However, the precise mechanisms underlying progressive hypoxia-induced glomerular injury remain unclear.
METHODS
We housed db/db mice in a hypoxia chamber (12% O2) for up to 16 weeks beginning at 8 weeks of age. Various urine, serum and kidney abnormalities and glomerular messenger RNA (mRNA) expression were compared with those in age-matched db/db mice housed under normoxia.
RESULTS
Levels of urinary albumin and podocalyxin (PCX) were significantly higher in hypoxic mice early during hypoxia. Ultracentrifugation of urine samples revealed that podocytes in the hypoxic mice shed PCX-positive microparticles into the urine. After 16 weeks of hypoxia, the mice also had higher hematocrits with lower serum glucose and various degrees of mesangiolytic glomerulosclerosis with microaneurysms and the infrequent occurrence of nodular lesions. Immunohistologically, hypoxic mice showed significantly decreased endothelial cell densities early during hypoxia and decreased podocyte densities later. In both hypoxic and normoxic mice, glomerular macrophage and transforming growth factor-β1 (TGF-β1) staining significantly increased with aging, without changes in vascular endothelial growth factor or endothelial nitric oxide synthase (eNOS). Glomerular mRNA expression of monocyte chemoattractant protein-1, eNOS and TGF-β1 was significantly enhanced in the hypoxic mice.
CONCLUSIONS
These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.
Identifiants
pubmed: 32596728
pii: 5864515
doi: 10.1093/ndt/gfaa074
doi:
Substances chimiques
Tgfb1 protein, mouse
0
Transforming Growth Factor beta1
0
Vascular Endothelial Growth Factor A
0
Nitric Oxide Synthase Type III
EC 1.14.13.39
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1678-1688Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.