Glibenclamide prevents increased extracellular matrix formation induced by high glucose concentration in mesangial cells.
Other than stimulation of cell contractility, little is known about the potential metabolic effects induced by sulfonylureas, independently of insulin action. Previous studies from our laboratory demonstrated complete abrogation of glomerulosclerosis in an experimental model of type 1 diabetes chronically (9 mo) treated with low-dose sulfonylureas (Biederman JI, Vera E, Pankhaniya R, Hassett C, Giannico G, Yee J, Cortes P. Kidney Int 67: 554-565, 2005). Therefore, the effects of glibenclamide (Glib) on net collagen I, collagen IV, and fibronectin medium net secretion and cell layer collagen I deposition were investigated in mesangial cells continuously exposed to 25 mM glucose for 8 wk and treated with predetermined increasing concentrations of Glib for the same period. Clinically relevant concentrations (0.01 microM) of Glib fully suppressed the high glucose-enhanced accumulation of collagen I, collagen IV, and fibronectin in the medium and inhibited collagen I deposition in the cell layer. These effects occurred while transforming growth factor (TGF)-beta1 medium concentration remained elevated and glucose uptake was increased to levels above those in 25 mM glucose-incubated cultures. The decreased collagen I accumulation occurred simultaneously with enhanced collagen I mRNA expression in concert with marked suppression of plasminogen inhibitor type-1 (PAI-1) mRNA and protein expression. This strongly suggests an accelerated matrix turnover favoring breakdown. Glib-induced effects demonstrated a biphasic pattern, being absent or reversed in cells treated with higher Glib concentrations (0.1 or 1 microM). Therefore, chronic Glib treatment at low concentrations markedly diminishes the high glucose-induced enhanced accumulation of extracellular matrix components by suppression of steady-state PAI-1 transcriptional activity. These results and those previously reported in vivo suggest that long-term Glib treatment may prevent glomerulosclerosis in insulin-deficient diabetes.
Giannico
Giovanna
G
Div. of Nephrology and Hypertension, Dept. of Medicine, Henry Ford Hospital, Clara Ford Pavilion-5, 2799 West Grand Blvd., Detroit, MI 48202, USA.
Cortes
Pedro
P
Baccora
Mohammed H
MH
Hassett
Clare
C
Taube
David W
DW
Yee
Jerry
J
D000199:Actins / Q000235:genetics; D000818:Animals; D001693:Biological Transport, Active; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003470:Culture Media; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003928:Diabetic Nephropathies / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050527:Mesangial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D024141:Collagen Type IV; D003470:Culture Media; D005353:Fibronectins; D051246:Glucose Transport Proteins, Facilitative; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D004247:DNA; D005947:Glucose; D005905:Glyburide