Ganglioside GM3 inhibits the high glucose- and TGF-beta1-induced proliferation of rat glomerular mesangial cells.
Abrupt proliferation of glomerular mesangial cells (GMCs) is a common feature in the early stage of diabetic glomerulopathy, and ganglioside GM3 (NeuAcalpha3Galbeta4Glcbeta1Cer) is thought to regulate the proliferation of many cell types. Recently, we have reported ganglioside GM3 as a modulator of glomerular hypertrophy in streptozotocin-induced diabetic rats []. This study examined whether modulation of cellular ganglioside GM3 could regulate the high glucose- and transforming growth factor-beta1 (TGF-beta1)-induced proliferation of GMCs. To pharmacologically modulate the cellular ganglioside GM3, GMCs originated from rat kidneys were cultured with exogenous ganglioside GM3 or d-threo-PDMP, an inhibitor of ganglioside synthesis, in the RPMI 1640 media containing normal (5.6 mM, NG) or high (25 mM, HG) glucose. HG, TGF-beta1 (10 ng/ml) and d-threo-PDMP (20 microM) significantly stimulated the mesangial cell proliferation, whereas these increments were remarkable attenuated by exogenous ganglioside mixture (0.1-0.2 mg/ml) or GM3 (20-100 microM) in a dose-dependent manner. The mesangial cell proliferation caused by HG, TGF-beta1 and d-threo-PDMP was closely correlated with decreases in both cellular sialic acid contents and ganglioside GM3 synthase activity. Based upon the mobility on high-performance thin-layer chromatography (HPTLC), GMCs showed a complex pattern of ganglioside expression that consisted, at least, of five different components of gangliosides, mainly ganglioside GM3. HG, TGF-beta1 and d-threo-PDMP induced a significant reduction of ganglioside expression with apparent changes in the composition of ganglioside GM3, and semi-quantitative analysis by HPTLC showed that ganglioside GM3 expression reduced to about 35-54% of control. These results provide a pathophysiological link between mesangial cell proliferation and ganglioside GM3 expression, indicating that exogenously added ganglioside GM3 inhibits the high-ambient glucose- and TGF-beta1-induced proliferation of cultured GMCs.
Kwak
Dong Hoon
DH
Division of Biological Science, College of Natural Sciences, Wonkwang University, Jeonbuk 570-749, Korea.
Lee
Seoul
S
Kim
Sung Jo
SJ
Ahn
Seon Ho
SH
Song
Ju Hung
JH
Choo
Young Kug
YK
Choi
Bong Kyu
BK
Jung
Kyu Yong
KY
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005679:G(M3) Ganglioside / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D005679:G(M3) Ganglioside; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005947:Glucose