Adenine at lower doses acts in the kidney as an aquaretic agent and prevents hyponatremia

Abstract

We have previously reported that adenine at high doses interferes with the vasopressin signaling pathway, causes massive diuresis and volume depletion, and ultimately leads to renal failure. In the present study, we examined the effects of adenine on renal salt and water handling in a time course and dose-response study in rats housed in metabolic cages and fed control or adenine-containing diet at 1500, 2000, 2500 mg/kg and euthanized after 1, 3, and 7 weeks. Adenine at 2000 and 2500 mg/kg caused early and significant polyuria, polydipsia, and decreased urine osmolality in a dose-dependent manner without significantly affecting food intake, blood volume, blood electrolyte levels, or acid-base composition. The impaired water balance resulted from the downregulation of apical water channel AQP2 in the outer and inner medulla but not in the cortex. Adenine did not alter electrolytes (Na⁺, K⁺, Cl^-) excretion at these doses for up to 3 weeks. However, a slight but significant increase in salt excretion was observed in adenine-fed rats for 7 weeks, which correlates with a significant downregulation of NKCC2, mostly in rats fed 2500 mg/kg adenine. Adenine-fed rats exhibited a substantial resistance to vasopressin in response to water deprivation or vasopressin treatment. Lastly, 2500 mg/kg adenine prevented the development of hyponatremia in a rat experimental model of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In conclusion, adenine acts as an aquaretic agent in the kidney at lower doses and during a short feeding period. It can be used as a vasopressin antagonist in conditions associated with hyponatremia.

Keywords: AQP2; Adenine; Aquaresis; Hyponatremia; Vasopressin resistance.