Lipoprotein(a) stimulates growth of human mesangial cells and induces activation of phospholipase C via pertussis toxin-sensitive G proteins.
BACKGROUND
Renal disease is commonly associated with hyperlipidemia and correlates with glomerular accumulation of atherogenic lipoproteins, for example, lipoprotein(a) [Lp(a)], and mesangial hypercellularity. Specific binding of Lp(a) to mesangial cells and induction of c-myc and c-fos expression has been demonstrated. Therefore, in this study, we investigated a possible growth stimulatory effect and mode of action of Lp(a) in human mesangial cells.


METHODS
Lp(a) was purified from the regenerate fluid of a dextran sulfate column-based low-density lipoprotein apheresis system. Human mesangial cells were isolated by a sequential sieving technique from patients undergoing tumor nephrectomy. DNA synthesis was measured by [3H]-thymidine incorporation. The intracellular calcium concentration ([Ca2+]i) was determined by Fura 2-fluorescence, and inositol 1,4,5-trisphosphate (1,4,5-IP3) concentration was measured by a radioreceptor assay.


RESULTS
The data show that Lp(a) bound to the cells with a Kd of 17.0 micrograms/ml and increased DNA synthesis and cell proliferation. Lp(a) caused a rapid increase in 1,4,5-IP3 and [Ca2+]i via a pertussis toxin-sensitive mechanism. The phospholipase C (PLC) inhibitor U73122 abolished Lp(a)-induced cell proliferation. In contrast, vasopressin-induced increase in 1,4,5-IP3 and [Ca2+]i was pertussis toxin insensitive.


CONCLUSIONS
This study revealed that Lp(a) stimulates growth of human mesangial cells. Lp(a)-induced signaling involves binding to a receptor and stimulation of PLC via Gi proteins. Stimulation of PLC appears to be essential for the growth stimulatory effect of Lp(a). Whether these effects of Lp(a) contribute to the pathophysiology of renal disease needs to be determined.
Mondorf
U F
UF
Department of Thoracic Surgery, Johann Wolfgang Goethe-University, Frankfurt, Germany. mondorf@em.uni-frankfurt.de
Piiper
A
A
Herrero
M
M
Olbrich
H G
HG
Bender
M
M
Gross
W
W
Scheuermann
E
E
Geiger
H
H
D001798:Blood Proteins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D017270:Lipoprotein(a) / Q000378:metabolism / Q000494:pharmacology*; D037342:Pertussis Toxin; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014667:Vasopressins / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001798:Blood Proteins; D004963:Estrenes; D017270:Lipoprotein(a); D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D010566:Virulence Factors, Bordetella; D014667:Vasopressins; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D004533:Egtazic Acid; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium