Dapagliflozin Stimulates Renal Ammonia Excretion in Rats

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs that induce glycosuria and are used to treat type 2 diabetes mellitus, moreover it has also been used in other conditions such as heart failure and atherosclerosis. However, little is known about the effects of these drugs on renal function. Considering that the maintenance of acid-base balance is closely related to renal physiology, in this study we evaluated the influence of chronic use of dapagliflozin on global renal function and urinary excretion of ammonia and titratable acids. Objective: To evaluate global renal function and urinary acid excretion (ammonia and titratable acid) in male Wistar rats chronically treated with dapagliflozin. Methods: 3-month-old male Wistar rats were randomized to control (C) and dapagliflozin (D) groups. Animals in group D received dapagliflozin (3 mg/kg, gavage) for 4 weeks. All animals were given food and water ad libitum throughout the experimental protocol. At 4 months of age, animals were placed in metabolic cages for 24-hour urine collection followed by blood sampling. Plasma concentrations of creatinine, sodium, potassium, urea, pH, pCO2, and bicarbonate were evaluated. The following were also evaluated: body weight, water intake, urine flow, and excretion of ammonia, titratable acids, glucose, and protein. Protocol approved by CEUA-UNIFESP number: 5985180423. Values expressed as mean ± standard error; number of animals per group: 6. Results: No significant changes were observed in blood gas parameters: pH (C: 7.33±0.043; D: 7.36±0.027), pCO2 (C: 53.30±2.40; D: 52.67±3.63 mmHg) and HCO3− (C: 27.07±1.31; D: 29.75±1.72 mEq/L) and no significant changes in plasma creatinine concentration (C: 0.41±0.04; D: 0.40±0.04mg/dl), Na+ (C: 144±0.47; D: 137±2.04 mmol/l) and K+ (C: 4.30±0.21; D: 4.16±0.20 mmol/l). We observed a significant increase in urine flow (C: 0.027±0.006; D: 0.068±0.005 mL/min/kg), possibly associated with intense glycosuria (C: 0.017±0.005; D: 8.97±0.51 g/24h). The significant increase in plasma urea concentration (C: 39.17±2.57; D: 48.83±1.27 mg/dL) and proteinuria (C: 11.04±0.30; D: 15.79±0.56 mg/24h) may indicate some renal impairment. Considering the marked increase in urinary excretion of ammonia (C: 0.65±0.05; D: 3.49±2.31 mEq/24h) and titratable acids (C: 0.180±0.036; D: 0.628±0.078 mEq/24h), we can conclude that the drug-induced glycosuria may lead to biochemical adaptations to maintain blood glucose levels within the normal range, at the expense of increased metabolic acid production. However, further experiments are needed to confirm this hypothesis. CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.