Abstract
Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase ameliorate glomerular pathology and renal dysfunction in different models of glomerular disease. This effect has generally been attributed to a decrease in the circulating levels of cholesterol. Focal or diffuse mesangial cell proliferation is a common feature of glomerular pathology. There is now evidence from studies in vitro and in vivo that platelet-derived growth factor (PDGF) is an important mediator of glomerular hypercellularity. The activity of HMGCoA reductase has previously been shown to be a requirement for cell growth. In the present study, we examined the effect of simvastatin, an HMGCoA reductase inhibitor, on PDGF-induced DNA synthesis and PDGF B chain gene expression in human glomerular mesangial cells. In addition, we investigated the effect of simvastatin on phospholipase C (PLC) and protein kinase C (PKC) activation stimulated by PDGF. We demonstrate that treatment of the cells with simvastatin completely inhibits PDGF-induced DNA synthesis. This inhibition is reversed by mevalonate but not by cholesterol or farnesol, two major metabolites of the mevalonate pathway. On the other hand inhibition of HMGCoA reductase does not influence PDGF-induced activation of PLC and PKC, or PDGF B chain gene expression. These data suggest that simvastatin acts at a late step in the PDGF mitogenic pathway without interfering with other early cellular responses elicited by this growth factor. These studies also raise the possibility that the ameliorative effect of HMGCoA reductase inhibitors on glomerular pathology may be mediated, at least in part, by a direct cellular effect.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 503-508 |
| Number of pages | 6 |
| Journal | Kidney International |
| Volume | 44 |
| Issue number | 3 |
| State | Published - Sep 1993 |
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ASJC Scopus subject areas
- Nephrology
Cite this
Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. / Grandaliano, Giuseppe; Biswas, Purba; Ghosh-choudhury, Goutam; Abboud, Hanna E.
In: Kidney International, Vol. 44, No. 3, 09.1993, p. 503-508.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells
AU - Grandaliano, Giuseppe
AU - Biswas, Purba
AU - Ghosh-choudhury, Goutam
AU - Abboud, Hanna E.
PY - 1993/9
Y1 - 1993/9
N2 - Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase ameliorate glomerular pathology and renal dysfunction in different models of glomerular disease. This effect has generally been attributed to a decrease in the circulating levels of cholesterol. Focal or diffuse mesangial cell proliferation is a common feature of glomerular pathology. There is now evidence from studies in vitro and in vivo that platelet-derived growth factor (PDGF) is an important mediator of glomerular hypercellularity. The activity of HMGCoA reductase has previously been shown to be a requirement for cell growth. In the present study, we examined the effect of simvastatin, an HMGCoA reductase inhibitor, on PDGF-induced DNA synthesis and PDGF B chain gene expression in human glomerular mesangial cells. In addition, we investigated the effect of simvastatin on phospholipase C (PLC) and protein kinase C (PKC) activation stimulated by PDGF. We demonstrate that treatment of the cells with simvastatin completely inhibits PDGF-induced DNA synthesis. This inhibition is reversed by mevalonate but not by cholesterol or farnesol, two major metabolites of the mevalonate pathway. On the other hand inhibition of HMGCoA reductase does not influence PDGF-induced activation of PLC and PKC, or PDGF B chain gene expression. These data suggest that simvastatin acts at a late step in the PDGF mitogenic pathway without interfering with other early cellular responses elicited by this growth factor. These studies also raise the possibility that the ameliorative effect of HMGCoA reductase inhibitors on glomerular pathology may be mediated, at least in part, by a direct cellular effect.
AB - Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase ameliorate glomerular pathology and renal dysfunction in different models of glomerular disease. This effect has generally been attributed to a decrease in the circulating levels of cholesterol. Focal or diffuse mesangial cell proliferation is a common feature of glomerular pathology. There is now evidence from studies in vitro and in vivo that platelet-derived growth factor (PDGF) is an important mediator of glomerular hypercellularity. The activity of HMGCoA reductase has previously been shown to be a requirement for cell growth. In the present study, we examined the effect of simvastatin, an HMGCoA reductase inhibitor, on PDGF-induced DNA synthesis and PDGF B chain gene expression in human glomerular mesangial cells. In addition, we investigated the effect of simvastatin on phospholipase C (PLC) and protein kinase C (PKC) activation stimulated by PDGF. We demonstrate that treatment of the cells with simvastatin completely inhibits PDGF-induced DNA synthesis. This inhibition is reversed by mevalonate but not by cholesterol or farnesol, two major metabolites of the mevalonate pathway. On the other hand inhibition of HMGCoA reductase does not influence PDGF-induced activation of PLC and PKC, or PDGF B chain gene expression. These data suggest that simvastatin acts at a late step in the PDGF mitogenic pathway without interfering with other early cellular responses elicited by this growth factor. These studies also raise the possibility that the ameliorative effect of HMGCoA reductase inhibitors on glomerular pathology may be mediated, at least in part, by a direct cellular effect.
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UR - http://www.scopus.com/inward/citedby.url?scp=0027181537&partnerID=8YFLogxK
M3 - Article
C2 - 8231022
AN - SCOPUS:0027181537
VL - 44
SP - 503
EP - 508
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 3
ER -