Vascular factors altered in glucose-treated mesangial cells and diabetic glomeruli. Changes in vascular factors impair endothelial cell growth and matrix.
We studied the effect of a high glucose (HG) environment on the vascular factors that are secreted by mesangial cells, and regulate endothelial growth and mesangial matrix deposition. To this effect, we measured the vascular factors in the glomeruli of streptozotocin-induced diabetic kidneys and in mesangial cells exposed to a HG concentration. We then transferred the media of mesangial cells previously exposed to high glucose to cultured endothelial cells to study the effects on endothelial growth, matrix formation, and in vitro capillary proliferation. In 1-week diabetic kidneys, glomerular vascular endothelial growth factor (VEGF) and angiopoietin-1 were inhibited by 38 and 57%, respectively, but angiopoietin-2 was increased by 318%. We found similar results in mesangial cells exposed to HG. There was a decrease of VEGF (50% by enzyme immunoassay, 27% by mRNA), decrease of angiopoietin-1 (65% by mRNA), and a much greater increase of angiopoietin-2 (280% by immunoassay, 523% by mRNA). Compared to controls, the media of mesangial cells previously exposed to HG impaired endothelial cell growth by 61%, increased extracellular matrix by 100%, and decreased capillary formation by 90%. We conclude that high ambient glucose alters the secretion of vascular factors elaborated by mesangial cells, resulting in an expansion of the endothelial cell matrix and disruption of capillary structure.
Singh
Ashok K
AK
Hektoen Institute for Medical Research, Chicago, IL 60612, USA. singashok@aol.com
Gudehithlu
Krishnamurthy P
KP
Pegoraro
Alfredo A
AA
Singh
Gogi K
GK
Basheerudin
Khaja
K
Robey
Robert B
RB
Arruda
Jose A L
JA
Dunea
George
G
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D018076:DNA, Complementary / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D017077:Culture Media, Conditioned; D018076:DNA, Complementary; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D005947:Glucose