Stimulation of renal gluconeogenesis by inhibition of the sodium pump

Abstract

1. 1. Ouabain (0.1–4 mM) stimulates glucose formation by isolated kidney tubules and kidney cortex slices from pyruvate, lactate, propionate and fructose by 10–40%. A stimulation of renal gluconeogenesis from pyruvate, lactate and propionate to a similar degree as obtained with ouabain is also observed in the presence of L-epinephrine (0.03–30 μM) or N 6-2- O-dibutyryl adenosine 3′,5′-monophosphate (dibutyryl-cyclic AMP) 1 mM). The diuretics ethacrynic acid (0.25 nM–2.5μM) and furosemide (0.01–10 μg/ml) also stimulate renal gluconeogenesis from pyruvate by 10–12%. 2. 2. Ouabain increased 14CO 2 fixation from the substrates pyruvate, lactate and fructose. Glycolysis remained unaffected by ouabain. 3. 3. In contrast to L-epinephrine, not stimulation but inhibition of gluconeogenesis was observed in the presence of ouabain with glutamate and dicarbonic acids as substrates. A different metabolite profile was obtained in the presence of ouabain and L-epinephrine or dibutyryl cyclic AMP. The stimulatory action of ouabain on renal gluconeogenesis was additive to the stimulatory action of L-epinephrine, dibutyryl cyclic AMP or acetoacetate. 4. 4. Ouabain did not change the activities of adenylate cyclase and phosphodiesterase in the kidney cortex. 5. 5. Ouabain led to an increase in intracellular Na + content, tissue K + concentration being unchanged. 6. 6. High extracellular K + concentrations caused an inhibition of gluconeogenesis in the controls, which was completely prevented by ouabain, although tissue K + contents increased to the same extent in the presence and in the absence of ouabain. 7. 7. Ouabain led to an inhibition of oxygen uptake and to a reduction of 14CO 2-formation from [2- 14C]pyruvate and [1- 14C]palmitate in the absence and presence of 1 mM carnitine, as well as to increased tissue levels of malate, lactate and α-ketoglutarate. Tissue ATP concentration remained unchanged or increased at high extracellular K + concentrations in the presence of ouabain. 8. 8. It is concluded, that ouabain exerts its stimulatory action on renal gluconeogenesis by inhibition of the sodium pump. Regulation of gluconeogenesis via changes of intracellular cation concentrations is excluded. It is assumed that inhibition of the Na + pump induces a higher energy state of the cell, which in turn favours energy-requiring synthetic processes.