Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy.
BACKGROUND
Vascular endothelial growth factor (VEGF) and its receptors have been implicated in the pathogenesis of diabetic nephropathy. The objective of this study was to determine whether alterations of the plasma and urinary VEGF and sFLT-1 levels were related to the stages and risk factors of diabetic nephropathy. In addition, we also examined the regulation of the VEGF/sFLT-1 expression by various stimuli in cultured human proximal tubule cells (HPTC).


METHODS
A total of 107 type 2 diabetic patients and 47 healthy control subjects were studied. The expression and protein levels of VEGF and sFLT-1 were measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA).


RESULTS
The urinary VEGF and sFLT-1 excretions were significantly increased in the microalbuminuric and proteinuric diabetic patients. The urinary VEGF levels were positively correlated with the urinary albumin to creatinine ratio (ACR), urinary sFLT-1 levels, and negatively correlated with creatinine clearance. The urinary sFLT-1 levels also showed a positive relationship with the urinary ACR. In cultured HPTC, high glucose stimuli rapidly up-regulated VEGF synthesis without having any effect on sFLT-1 synthesis. Interestingly, angiotensin II (Ang II) induced a dose-dependent increase in the synthesis of both VEGF and sFLT-1, which was significantly blocked by losartan.


CONCLUSIONS
The urinary excretion of VEGF and sFLT-1 increased at a relatively early stage in diabetic nephropathy associated with urinary albumin excretion. A marked increase in both VEGF/sFLT-1 synthesis in response to Ang II was observed in HPTC, which was different from the response to glucose stimuli. These findings may imply that VEGF and sFLT-1 can actively take part in the pathogenesis of diabetic nephropathy.
Kim
Nan Hee
NH
Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, Republic of Korea.
Oh
Jeong Heon
JH
Seo
Ji A
JA
Lee
Kye Won
KW
Kim
Sin Gon
SG
Choi
Kyung Mook
KM
Baik
Sei Hyun
SH
Choi
Dong Seop
DS
Kang
Young Sun
YS
Han
Sang Youb
SY
Han
Kum Hyun
KH
Ji
Yi Hwa
YH
Cha
Dae Ryong
DR
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D004247:DNA / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D040281:Vascular Endothelial Growth Factor Receptor-1
D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D004247:DNA; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D005947:Glucose