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      Transactivation of the Epidermal Growth Factor Receptor by Angiotensin II in Glomerular Podocytes

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          Background/Aims: Activation of angiotensin II (ANG2) receptors stimulates extracellular signal-regulated kinases (ERKs) that, in some cell systems, are mediated by transactivating the epidermal growth factor (EGF) receptor (EGFR) through mechanisms involving matrix metalloprotease (MMP)-stimulated processing of heparin-binding EGF (HB-EGF) from its precursor. Methods: The signaling pathways linked to ANG2-dependent ERK activation were determined in an immortalized mouse podocyte cell line by monitoring ANG2-stimulated phosphorylation of ERK1/2. Results: ANG2 induced transient ERK phosphorylation that was maximal at 5 min and then rapidly dissipated. ANG2-dependent ERK activation was inhibited by: (1) the type-1 ANG2-selective antagonist losartan; (2) the type-2 ANG2-selective antagonist PD123319; (3) an inhibitor of MMP2/9; (4) the EGFR kinase inhibitor AG1478, and (5) the HB-EGF antagonists CRM197 and heparin. ANG2-dependent ERK activation was mediated by both protein kinase C (PKC)- and calcium-dependent mechanisms and was associated with tyrosine phosphorylation of EGFR. To determine if ANG2-dependent HB-EGF release could act in a paracrine fashion on adjacent cells, HEK293 cells were stably transfected with green fluorescent protein-tagged ERK2 (GFP-ERK2). In stably transfected HEK293 cells, EGF stimulated phosphorylation of endogenous ERK1/2 as well as GFP-ERK2. In contrast, ANG2 had no effect on ERK phosphorylation in stably transfected HEK293 cells. When podocytes were co-cultured with stably transfected HEK293 cells, however, treatment with ANG2 rapidly stimulated GFP-ERK2 phosphorylation. Both the MMP2/9 inhibitor and AG1478 attenuated ANG2-dependent phosphorylation of GFP-ERK2 in the co-culture system. Conclusions: These data indicate that ERK activation is induced by ANG2 in podocytes by mechanisms involving ANG2-dependent release of HB-EGF which, in turn, may act in an autocrine and paracrine fashion to stimulate ERK activity.

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          Most cited references 29

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          Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1.

          Glomerulonephritis is an inflammation of the kidney characterized by the accumulation of extracellular matrix within the damaged glomeruli, impaired filtration and proteinuria. In its progressive form, the disease destroys kidney function leading to uraemia and death, unless dialysis therapy or kidney transplantation is available. The pathogenesis of glomerulonephritis is incompletely understood, but the eliciting factor is thought often to be an immunological injury to mesangial and/or other resident cells in the glomeruli. We have used an animal model of acute mesangial proliferative glomerulonephritis to show that this disease is associated with increased production and activity of transforming growth factor beta 1 (TGF-beta 1), an inducer of extracellular matrix production. Here we report that administration of anti-TGF-beta 1 at the time of induction of the glomerular disease suppresses the increased production of extracellular matrix and dramatically attenuates histological manifestations of the disease. These results provide direct evidence for a causal role of TGF-beta 1 in the pathogenesis of the experimental disease and suggest a new approach to the therapy of glomerulonephritis.
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            Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity.

            G protein-coupled receptors (GPCRs) can stimulate the mitogen-activated protein kinase (MAPK) cascade and thereby induce cellular proliferation like receptor tyrosine kinases (RTKs). Work over the past 5 years has established several models which reduce the links of G(i)-, G(q)-, and G(s)-coupled receptors to MAPK on few principle pathways. They include (i) Ras-dependent activation of MAPK via transactivation of RTKs such as the epidermal growth factor receptor (EGFR), (ii) Ras-independent MAPK activation via protein kinase C (PKC) that converges with the RTK signalling at the level of Raf, and (iii) activation as well as inactivation of MAPK via the cAMP/protein kinase A (PKA) pathway in dependency on the type of Raf. Most of these generalizing hypotheses are founded on experimental data obtained from expression studies and using a limited set of individual receptors. This review will compare these models with pathways to MAPK found for a great variety of peptide hormone and neuropeptide receptor subtypes in various cells. It becomes evident that under endogenous conditions, the transactivation pathway is less dominant as postulated, whereas pathways involving isoforms of PKC and, especially, phosphoinositide 3-kinase (PI-3K) appear to play a more important role as assumed so far. Highly cell-specific and unusual connections of signalling proteins towards MAPK, in particular tumour cells, might provide points of attacks for new therapeutic concepts.
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              Activation of MAPKs by angiotensin II in vascular smooth muscle cells. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK.

              In cultured vascular smooth muscle cells (VSMC), the vasculotrophic factor, angiotensin II (AngII) activates three major MAPKs via the G(q)-coupled AT1 receptor. Extracellular signal-regulated kinase (ERK) activation by AngII requires Ca(2+)-dependent "transactivation" of the EGF receptor that may involve a metalloprotease to stimulate processing of an EGF receptor ligand from its precursor. Whether EGF receptor transactivation also contributes to activation of other members of MAPKs such as p38MAPK and c-Jun N-terminal kinase (JNK) by AngII remains unclear. In the present study, we have examined the effects of a synthetic metalloprotease inhibitor BB2116, and the EGF receptor kinase inhibitor AG1478 on AngII-induced activation of MAPKs in cultured VSMC. BB2116 markedly inhibited ERK activation induced by AngII or the Ca(2+) ionophore without affecting the activation by EGF or PDGF. BB2116 as well as HB-EGF neutralizing antibody inhibited the EGF receptor transactivation by AngII, suggesting a critical role of HB-EGF in the metalloprotease-dependent EGF receptor transactivation. In addition to the ERK activation, activation of p38MAPK and JNK by AngII was inhibited by an AT1 receptor antagonist, RNH6270. and EGF markedly activate p38MAPK, whereas but not EGF markedly activates JNK, indicating the possible contribution of the EGF receptor transactivation to the p38MAPK activation. The findings that both BB2116 and AG1478 specifically inhibited activation of p38MAPK but not JNK by AngII support this hypothesis. From these data, we conclude that ERK and p38MAPK activation by AngII requires the metalloprotease-dependent EGF receptor transactivation, whereas the JNK activation is regulated without involvement of EGF receptor transactivation.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 2006
                22 March 2006
                : 103
                : 3
                : e109-e118
                Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, N.C., USA
                92196 Nephron Exp Nephrol 2006;103:e109–e118
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 55, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/92196
                Original Paper


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