Visit our Expo - Redox and Inflammation signaling 2012

Cross-talk between angiotensin II and glucagon receptor signaling mediates activation
of mitogen-activated protein kinases ERK 1/2 in rat glomerular mesangial cells.
Xiao C. Li, Oscar A. Carretero, and Jia L. Zhuo.
Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI
48202, USA. E-mail: xcli1@hfhs.org
Agonist-induced phosphorylation of MAP kinases extracellular signal-regulated protein
kinases 1 and 2 (p-ERK 1/2) plays an important role in the regulation of cell differentiation,
transformation and proliferation. We hypothesized that angiotensin II (Ang II), glucagon and
high glucose (HG) induce ERK 1/2 phosphorylation in cultured rat glomerular mesangial cells
via cross-talk between their signaling pathways. Ang II (1 nM), glucagon (1 nM) and high
glucose (HG, 25 mM) induced ERK 1/2 phosphorylation (Ang II: 174 ± 16%; glucagon: 214
± 14%; and HG: 190 ± 15%; p < 0.01 vs. control), and all responses were inhibited by the
AT 1 receptor blocker losartan (Ang II + losartan: 62 ± 21%; glucagon + losartan: 77 ± 14%;
and HG ± losartan: 98 ± 10%; p < 0.01 vs. Ang II, glucagon or HG). Pretreatment of
mesangial cells with a phospholipase C (PLC) inhibitor U73122 (10 -6 M), a cAMP-dependent
protein kinase A (PKA) inhibitor H89 (10 -6 M), or a phosphatidylinositol 3-kinase (PI 3kinase)
inhibitor wortmannin (10 -6 M), all markedly attenuated phosphorylation of ERK 1/2
induced by Ang II (Ang II + U73122: 111 ± 13%; Ang II + H89: 86 ± 10%; and Ang II +
wortmannin: 114 ± 8%; p < 0.01 vs. Ang II), glucagon (glucagons + U73122: 109 ± 15%;
glucagon + H89: 113 ± 16%; and glucagons + wortmannin: 115 ± 9%; p < 0.01 vs. glucagon)
and HG (HG + U73122: 90 ±18%; HG + H89: 117 ± 7%; and HG + wortmannin: 139 ± 11%;
p < 0.01 vs. HG). These results suggest that AT 1 receptor-activated PLC, cAMP-dependent
PKA and PI 3-kinase signaling pathways mediate Ang II-, glucagon- and hyperglycemiainduced
MAP kinases ERK 1/2 phosphorylation in glomerular mesangial cells. Parts of this
work were supported by a grant from National Institutes of Health (RO1DK067299).
Addendum: A list of recent publications
Widdop, R.E., X.C. Li, and B. Jarrott. Regional haemodynamic effects of AT1 angiotensin II
receptor antagonist, CV-11974, in conscious rats. Blood Press. 3 (Suppl 5): 15-20, 1994.
Li, X.C., and R.E. Widdop. Regional hemodynamic effects of angiotensin II AT1 receptor
antagonist, CV-11974, in conscious renal hypertensive rats. Hypertension 26: 989-997, 1995.
Li, X.C., and R.E. Widdop. Angiotensin type 1 receptor antagonists CV-11974 and EXP 3174
cause selective renal vasodilatation in conscious spontaneously hypertensive rats. Clin. Sci.
91: 147-154, 1996.
Widdop, R.E., and X.C. Li. A simple versatile method for measuring tail cuff systolic blood
pressure in conscious rats. Clin. Sci. 93: 191-194, 1997.
Li, X.C., P.M. Beart, A.M. James, N.M. Nicole, and R.E. Widdop. Type I and II metabotropic
receptor agonists and antagonists evoke cardiovascular effects after intrathecal administration
in conscious rats. Br. J. Pharmacol. 128: 823-829, 1999.
Paull, J.R.A., X.C. Li, D.B. Sampey, and R.E. Widdop. Pharmacodynamic contribution to the
vasodilator effect of chronic AT1 receptor blockade in SHR. Hypertension 37: 91-98, 2001.
Rey, F.E., X.C. Li, O.A. Carretero, J.L. Garvin, and P.J. Pagano. Perivascular superoxide
anion contributes to impairment of endothelium-dependent relaxation. Role of gp91phox.
Circulation 106: 2497-2502, 2002.
Li, X.C., and R.E. Widdop. AT2 receptor-mediated vasodilatation is unmasked by AT1
receptor blockade in conscious SHR. Br. J. Pharmacol. 142: 821-830, 2004.
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