Abstract 12460: Coupling Factor 6 Induces Tissue Acidosis and Thereby Salt-Sensitive Hypertension with Diabetes by Rac1 Activation and Insulin Receptor Inactivation
Background: Despite advances in pharmacological treatments, diabetes and hypertension continue to be a major public health problem with high morbidity and mortality. We recently identified a circulating peptide coupling factor 6 (CF6) which binds to the molecular rotary motor F1Fo complex at the plasma membrane (ecto-F1Fo complex), resulting in proton import. We investigated whether overexpression of CF6 contributes to coexistence of diabetes and hypertension by intracellular acidosis.
Methods and Results: We generated two-fold CF6-overexpressing transgenic mouse (TG). Intracellular pH measured by 31P-magnetic resonance spectroscopy was decreased by 0.1 to 0.15 pH unit in the skeletal muscle (6.96±0.03 vs 7.05±0.02, p<0.05) and the liver (7.00±0.04 vs 7.16±0.04, p<0.05) in TG compared with wild type mice (WT). TG mice manifested both systolic blood pressure elevation by 20 mmHg (p<0.05) under a high salt diet and diabetes under a high sucrose diet compared with WT (glucose, 133±10 vs 108±1 mg/dl; insulin, 698±87 vs 295±55 pg/ml, both p<0.05). It was reported that Rac1, a member of the Rho family guanosine triphosphate (GTP) ases, activates aldosterone-induced mineralocorticoid receptor signaling. Pull-down assays revealed that the ratio of Rac1-GTP to total Rac1 was increased in the TG kidney compared with the WT kidney, and it was enhanced by extracellular acidosis and amiloride. Phospho-insulin receptor β (Tyr1150/1151) in the skeletal muscle and liver was decreased in TG compared with WT, but that in the adipose tissue was similar between TG and WT. Insulin receptor substrate (IRS)-1 in the skeletal muscle was decreased by 64±9% in TG compared with WT (n=5, p<0.05), and phospho-IRS-2 (panTyr) was decreased in the TG liver. Phosphoinositide 3-kinase activity and phospho-Akt1 (ser 473) in the skeletal muscle and liver were both decreased in TG compared with WT. Intraperitoneal administration of amiloride, an inhibitor of proton extruder, at 50 mg/kg for 2 days exacerbated insulin resistance, while anti-CF6 antibody ameliorated insulin resistance.
Conclusions: CF6 regulates cytosolic pH by interacting with ecto-F1Fo complex and may link hypertension with diabetes by Rac1 activation and insulin receptor inactivation due to tissue acidosis.
- © 2011 by American Heart Association, Inc.