Mitogenic signals for thrombin in mesangial cells: regulation of phospholipase C and PDGF genes.
Thrombin is a proteolytic enzyme of diverse biological activities, which is produced during activation of the coagulation pathway. In addition, thrombin is a mitogen for fibroblasts and endothelial cells. Intraglomerular thrombosis and cell proliferation are common pathological features of several glomerular diseases. We studied the effect of thrombin on deoxyribonucleic acid (DNA) synthesis in cultured human mesangial cells and explored mechanisms of signal transduction involved. Bovine and human thrombin caused dose-dependent increases in DNA synthesis, inositol trisphosphate, and cytosolic calcium [(Ca2+)i]. A threefold increase in inositol-3-trisphosphate (IP3) levels was observed as early as 10 s after the addition of thrombin, whereas increases in (Ca2+)i occurred within 5-10 s and declined rapidly. Stimulation of mesangial cells by thrombin resulted in induction of messenger ribonucleic acids (mRNAs) encoding platelet-derived growth factor (PDGF) A- and B-chains. This was associated with an enhanced secretion of PDGF-like protein. These data provide mechanisms by which thrombin may regulate mesangial cell function in disease states.
Shultz
P J
PJ
Department of Medicine, Veterans Administration Medical Center, Cleveland, Ohio.
Knauss
T C
TC
Mené
P
P
Abboud
H E
HE
D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008934:Mitogens / Q000494:pharmacology / Q000502:physiology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology*; D010738:Type C Phospholipases / Q000235:genetics*
D008934:Mitogens; D010716:Phosphatidylinositols; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D012333:RNA, Messenger; D010738:Type C Phospholipases; D013917:Thrombin; D002118:Calcium