Endothelial dysfunction as a modifier of angiogenic response in Zucker diabetic fat rat: amelioration with Ebselen.
BACKGROUND
Progression of nephropathy in metabolic syndrome is associated with microvasculopathy and vascular dropout.


METHODS
Eight- and 22-week-old Zucker diabetic fat (ZDF) and Zucker lean (ZL) rats were studied to characterize the progression of nephropathy, and to test the effect of a peroxynitrite scavenger, Ebselen, on renal microvasculature and angiogenic competence.


RESULTS
Capillary density was increased, both in the cortex (P < 0.05) and in the inner medulla (P < 0.001) by the age of 8 weeks, but significantly decreased (P < 0.01 and P < 0.001) by the age of 22 weeks in ZDF compared to ZL rats. Similarly, the angiogenic competence of cortical and medullary renal explants was increased in 8-week-old ZDF (P < 0.01), but decreased at 22 weeks (P < 0.001). Alterations of angiogenic competence in ZDF rats were associated with altered expression of vascular endothelial growth factor (VEGF), reduced expression of Flk-1, and neuropilin. Acetylcholine-induced relaxation of microdissected interlobar arteries from 8-week-old ZDF rats was unimpaired, but significantly attenuated in 22-week-old ZDF rats (P < 0.001). Treatment with Ebselen partially prevented the decrease in capillary density and angiogenic competence of renal explants, and restored acetylcholine-induced vasorelaxation in 22-week-old ZDF rats.


CONCLUSIONS
The progression of nephropathy in ZDF rats is associated with decreased angiogenic competence both ex vivo and in vivo. This is accompanied by a altered expression of VEGF system components and endothelial dysfunction, and scavenging peroxynitrite with Ebselen ameliorates the progression of microvasculopathy and partially restores angiogenesis. These findings reveal the complex mechanism of microvascular dropout in experimental metabolic syndrome.
Gealekman
Olga
O
Departments of Medicine, Pathology, and Pharmacology, New York Medical College, Valhalla, New York, USA.
Brodsky
Sergey V
SV
Zhang
Fan
F
Chander
Praveen N
PN
Friedli
Caline
C
Nasjletti
Alberto
A
Goligorsky
Michael S
MS
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D054833:Isoindoles; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D000109:Acetylcholine