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Abstract: SA-PO256

Exploring the Potential of Renal Dopaminergic System-Mediated Enhancement in Sodium Excretion by Canagliflozin

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Watanabe, Guy, Department of Nephrology and Hypertension, Fukushima Medical University School of Medicine, Fukushima, Fukushima, Japan
  • Horita, Shoichiro, Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Fukushima, Japan
  • Satoh, Mamoru, Ota Nishinouchi Byoin, Koriyama, Fukushima, Japan
  • Shigetomi, Shuichi, Futaba Kosei Hospital, Futaba, Japan
  • Shimomura, Kenju, Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Fukushima, Japan
  • Kazama, Junichiro James, Department of Nephrology and Hypertension, Fukushima Medical University School of Medicine, Fukushima, Fukushima, Japan
Background

We have found that the renal dopaminergic system starts to activate along with the onset of diabetes/diabetic nephropathy, leading to sodium excretion before the occurrence of polyurea using spontaneously diabetic SDT rats. We raised the question of whether the SGLT2 inhibitors exert the natriuretic effects via the renal dopaminergic system in non-diabetic SD rats.

Methods

Sprague-Dawley (SD) rats (9-11 weeks old, male, N = 8 for non-treated rats, N=7 for canagliflozin-treated rats) were fed a commercial rodent diet. Canagliflozin (1.5-2mg/kg/day) dissolved with 200-250 mL of drinking water were orally administered every morning, from 14 to 25 weeks of ages. Blood samples were collected from the tail vein every week from the ages of 13 to 25 weeks, after which the body weight and the glucose levels. Each rat was individually housed in a metabolic cage for 24 h every week from the ages of 13 to 25 weeks and collected urine samples. At 26 weeks of age, rats were euthanized, perfused intracardially with saline containing heparin (20 IU/mL) and paraformaldehyde (PFA) for histological analyses.

Results

The plasma sodium concentration and blood glucose levels were similar across groups. But significant differences were observed in urinary sodium excretion, urinary glucose excretion, demonstrating the efficacy of canagliflozin. In mass spectrometry imaging analyses, mean values of cortical ionized L-DOPA intensity in canagliflozin-treated SD rats were significantly higher than the L-DOPA in non-treated SD rats. Also, we have observed that canagliflozin-treated SD rats exhibit significantly higher levels of reduced glutathione compared to control SD rats, suggesting a potential contribution to the reduction of renal oxidative stress.

Conclusion

Although further study needs to be conducted, we speculate that each mechanism, the activation of renal dopaminergic system and the suppression of oxidative stress, is another possible mechanism for kidney protection brought about by SGLT2 inhibitors. Possibly, the increased cortical reduction of oxidative stress may contribute to the detoxification caused by excess amounts of L-DOPA and DA.