Inhibition of cGMP accumulation in mesangial cells by bradykinin and tyrosine kinase inhibitors.
We examined the effect of bradykinin (BK) on the accumulation of cGMP of the mesangial cell (MC), a smooth muscle-like cell of the renal glomerulus. BK caused a time- and concentration dependent reduction of the cGMP concentration. In addition, BK inhibited total protein tyrosine kinase (PTK) activity. Two tyrosine kinase inhibitors (TKI) genistein and tyrphostin also reduced the cGMP concentration. The inhibition of BK and TKI were not additive. The inhibition of PTK by BK, mediated through activation of the B2-receptor, was unaffected by inhibitors of Gi/o proteins, phospholipase C, protein kinase C, cyclooxygenase and Ca2+ release from intracellular stores. Only IBMX a broad spectrum inhibitor of phosphodiesterases (PDE) and 8-methoxymethyl IBMX a specific type-1 PDE inhibitor prevented the inhibitory effects of BK and TKI indicating the involvement of type-1 PDE. In addition, BK had no effect on soluble guanylate cyclase (sGC) and nitric oxide synthase activity. In freshly isolated glomeruli, which represent the physiological environment of MC, BK also reduced the cGMP concentration. Like in MC, the inhibitory effect was suppressed by IBMX. These data demonstrate that BK suppresses a PTK-dependent pathway of cGMP production in rat MC at a level downstream of NO synthase and sGC. It is suggested that BK and TKI inhibitors decrease cGMP levels by preventing tyrosine phosphorylation of type-1 PDE activity, thereby leading to enzyme activation.
Alric
C
C
Institut National de la Sante et de la Recherche Medicale U388, Institut Louis Bugnard, CHU Rangueil, 31403 Toulouse Cedex, France.
Pecher
C
C
Tack
I
I
Schanstra
J P
JP
Bascands
J L
JL
Girolami
J P
JP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000032:analysis / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020032:Tyrphostins / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D020032:Tyrphostins; D019833:Genistein; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D001920:Bradykinin; D015056:1-Methyl-3-isobutylxanthine