H⁺-ATPase blockade reduced renal gluconeogenesis and plasma glucose in a diabetic rat model

Vacuolar H⁺-adenosine triphosphatase (ATPase) plays important roles in urinary acid excretion, vesicular acidification to activate enzymes, and the membrane recycling of transporters in the kidney. As acidosis stimulates renal gluconeogenesis, we investigated the effect of blockade of H⁺-ATPase on renal gluconeogenesis in diabetic rats. Diabetes mellitus was induced by a single injection of streptozotocin, and a group of DM rats was treated with bafilomycin B1 intraperitoneally for 8 days. In diabetic rats, the renal expression and activity of H⁺-ATPase were increased with elevated urinary ammonium excretion. The blockade of H⁺-ATPase by bafilomycin B1 reduced the renal H⁺-ATPase activity and urinary ammonium excretion in diabetic rats. Treatment with bafilomycin suppressed the enhancement of the renal gluconeogenesis enzymes phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in diabetic rats and reduced the renal cytoplasmic glucose levels, whereas hepatic gluconeogenesis did not change significantly. After a 24-h starvation period, bafilomycin decreased the plasma glucose level to a normal level in diabetic rats. The suppression of renal gluconeogenesis by an H⁺-ATPase inhibitor may therefore be a new therapeutic target for the treatment of diabetes mellitus.