Long-term blockade of vascular endothelial growth factor receptor-2 aggravates the diabetic renal dysfunction associated with inactivation of the Akt/eNOS-NO axis.
Nephrol Dial Transplant
; 26(4): 1173-88, 2011 Apr.
Article
em En
| MEDLINE
| ID: mdl-20935017
ABSTRACT
BACKGROUND:
Diabetic nephropathy is characterized by abnormal angiogenesis, and this is driven by several factors, including hyperglycaemia and ischaemia. We investigated the role of vascular endothelial growth factor receptor-2 (VEGFR-2) blockade and its effects on diabetic nephropathy.METHODS:
Male db/db and db/m mice received long-term treatment with dRK6, an arginine-rich anti-VEGF hexapeptide, for 12 weeks or short-term treatment for only the first 4 weeks, starting from 8 weeks of age.RESULTS:
The urinary albuminuria and VEGF excretion varied according to the duration of diabetes, and the urinary VEGF levels were strongly correlated with the levels of albuminuria. Diabetes increased the VEGFR-2 expression in the kidneys. At the end of the 12-week study, compared with the db/db control mice, the db/db mice with long-term dRK6 treatment, which selectively inhibited VEGFR-2, had more albuminuria, related to weak nephrin signalling and advanced renal phenotypes, which were associated with hypoxia-oxidative stress, and an increased number of apoptotic endothelial cells. Interestingly, these changes were related to a decrease in phospho-Akt/eNOS-NO bioavailability. On the in vitro study, dRK6 increased the number of apoptotic human umbilical vein endothelial cells (HUVECs) in the high glucose media by blocking phospho-Akt/eNOS-NO signalling, and this was related to the increased oxidative stress. The short-term inhibition of VEGFR-2 neither improved the albuminuria nor the renal phenotype induced by diabetes.CONCLUSIONS:
Long-term selective blockade of VEGFR-2 by dRK6 had deleterious renal effects, and this was associated with downregulation of the Akt/eNOS-NO axis in db/db mice. Short-term VEGFR-2 blockade did not improve the renal phenotypes and the albuminuria. These findings suggest that VEGF-A-VEGFR-2 inhibition, regardless of how long it may be, does not ameliorate diabetic nephropathy in type 2 diabetes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Receptor 2 de Fatores de Crescimento do Endotélio Vascular
/
Diabetes Mellitus Tipo 2
/
Nefropatias Diabéticas
/
Insuficiência Renal
/
Óxido Nítrico Sintase Tipo III
/
Proteínas Proto-Oncogênicas c-akt
/
Óxido Nítrico
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Nephrol Dial Transplant
Assunto da revista:
NEFROLOGIA
/
TRANSPLANTE
Ano de publicação:
2011
Tipo de documento:
Article