Hormones – Cytokines – Signaling
Kidney International (2002) 62, 412–421; doi:10.1046/j.1523-1755.2002.00475.x
Inhibition of IGF-I–induced Erk 1 and 2 activation and mitogenesis in mesangial cells by bradykinin
Celine Alric, Christiane Pecher, Eric Cellier, Joost P Schanstra, Bruno Poirier, Jacques Chevalier, Jean-Loup Bascands and Jean-Pierre Girolami
INSERM U388, Institut Louis Bugnard, CHU Rangueil, Toulouse, and INSERM U430, Hôpital Broussais, Paris, France
Correspondence: Dr Jean-Pierre Girolami, INSERM U388, Institut Louis Bugnard, CHU Rangueil, 31403 Toulouse Cedex, France. E-mail: girolami@toulouse.inserm.fr
Received 15 August 2001; Revised 14 March 2002; Accepted 19 March 2002.
Abstract
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.
Keywords:
insulin-like growth factor, diabetic nephropathy, MAP kinase, tyrosine phosphatase, cell proliferation, glomerulosclerosis
