Inhibition of IGF-I-induced Erk 1 and 2 activation and mitogenesis in mesangial cells by bradykinin.
BACKGROUND
The beneficial effects of therapeutic angiotensin-converting enzyme (ACE) inhibitor treatment against the worsening of glomerulosclerosis during the course of diabetic nephropathy have been widely documented. ACE inhibitors inhibit both angiotensin II formation and bradykinin (BK) degradation, thereby reducing angiotensin II type 1 (AT1) receptor activity and favoring B2-kinin receptor (B2 receptor) activation. Since the involvement of growth factors such as insulin-like growth factor (IGF-I) has been implicated in the early steps of diabetic nephropathy, we investigated the effect of BK on Erk 1 and 2 activation and cell proliferation by IGF-I.


METHODS
The activation of Erk 1 and 2 in mesangial cells (MCs) and isolated glomeruli (IG) was investigated by immunoprecipitation and Western blotting during activation of the IGF-I receptor in the presence or absence of BK and of protein kinase C (PKC), tyrosine-kinase and phosphatase selective inhibitors. Mesangial cell proliferation was assessed in vitro by cell counting.


RESULTS
In untreated MCs and IG, when added separately, BK and IGF-I both activated Erk 1 and 2. In contrast, in MCs and IG pretreated with BK, the IGF-I-induced Erk 1 and 2 activation was dose-dependently reduced. The inhibitory effect of BK on IGF-I-induced activation of Erk 1 and 2 was completely abolished by addition of a B2 antagonist, by chelation of intracellular calcium and by tyrosine phosphatase inhibition. Additionally, BK reduced MC proliferation induced by IGF-I.


CONCLUSIONS
A new inhibitory pathway of the early steps of IGF-I signaling by the B2 receptor is found both in cultured MCs and in IG, which involves a calcium-dependent tyrosine phosphatase activity. Recruitment of this mechanism may account for the beneficial effects of ACE inhibitor treatment on glomerulosclerosis associated with diabetic nephropathies.
Alric
Celine
C
INSERM U388, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
Pecher
Christiane
C
Cellier
Eric
E
Schanstra
Joost P
JP
Poirier
Bruno
B
Chevalier
Jacques
J
Bascands
Jean-Loup
JL
Girolami
Jean-Pierre
JP
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology
D007334:Insulin-Like Growth Factor I; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D001920:Bradykinin; D002118:Calcium