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(Hypertension. 2006;47:580.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

Role of Protein Kinase A and Phospholipase C

From the Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Mich.

Correspondence to Jia L. Zhuo, Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202. E-mail jzhuo1{at}hfhs.org

Glucagon, a major insulin counterregulatory hormone, binds to specific G_s protein–coupled receptors to activate glycogenolytic and gluconeogenic pathways, causing blood glucose levels to increase. Inappropriate increases in serum glucagon play a critical role in the development of insulin resistance and target organ damage in type 2 diabetes. We tested the hypotheses that: (1) glucagon induces proliferation of rat glomerular mesangial cells through glucagon receptor–activated phosphorylation of mitogen-activated protein kinase extracellular signal–regulated kinase 1/2 (p-ERK 1/2); and (2) this phosphorylation involves activation of cAMP-dependent protein kinase A (PKA) and phospholipase C (PLC)/[Ca²⁺]_i signaling pathways. In rat mesangial cells, glucagon (1 nM) stimulated [³H]-thymidine incorporation by 96% (P<0.01). This proliferative effect was blocked by the specific glucagon receptor antagonist [Des-His¹-Glu⁹] glucagon (1 µmol/L; P<0.01), a mitogen-activated protein kinase/ERK kinase inhibitor PD98059 (10 µmol/L; P<0.01), a PLC inhibitor U73122 (1 µmol/L; P<0.01), or a PKA inhibitor H-89 (1 µmol/L; P<0.01). The proliferation was associated with a 2-fold increase in p-ERK 1/2 that peaked 5 minutes after glucagon stimulation (P<0.01) and also was blocked by [Des-His¹-Glu⁹] glucagon. Total ERK 1/2 was not affected by glucagon. Pretreating of mesangial cells with U73122 or H89 significantly attenuated ERK 1/2 phosphorylation induced by glucagon. We believe that these are the first data showing that glucagon activates specific receptors to induce ERK 1/2 phosphorylation and thereby increase mesangial cell proliferation and that this effect of glucagon involves both PLC/[Ca²⁺]_i- and cAMP-dependent PKA-activated signaling cascades.

Key Words: kidney • cyclic AMP • calcium • diabetes mellitus • glomerulosclerosis • insulin resistance

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