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Abstract: SA-PO446

Linagliptin Increases Urinary Sodium Excretion via Deactivating Renal Epithelial Sodium Channel (ENaC) in Diabetic Rodents and Patients with Diabetes Mellitus

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Kodama, Goh, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan
  • Taguchi, Kensei, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan
  • Ito, Sakuya, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan
  • Fukami, Kei, Kurume Daigaku Igakubu Daigakuin Igaku Kenkyuka, Kurume, Fukuoka, Japan
Background

About half of patients with diabetes mellitus (DM) develop hypertension, leading to further organ damage. ENaC activation is linked to hypertension. Whereas SGLT2 inhibitors have drawn attention to its renoprotective effect, there are still several anti-diabetic agents available in clinic. However, which agent is the best partner of SGLT2 inhibitors remains unknown. In the present study, we investigated whether linagliptin (LINA), a DPP4 inhibitor, coordinates with SGLT2 inhibitor to attenuate diabetic nephropathy (DM-N) and explored the synergetic effect of LINA in diabetic and hypertensive rodents as well as patients with DM.

Methods

[1] SDT-fatty rats, an obese DM model, were given high salt water and categorized into four groups as followings; Sham, DM-N, DM-N treated with Empagliflozin for 12 weeks (EMPA), DM-N treated with 6-week EMPA followed by 6-week treatment with linagliptin (EMPA + LINA). [2] DOCA/salt mice, an ENaC-activated hypertensive model, were treated with EMPA or EMPA + LINA to investigate if LINA regulates ENaC activation. [3] Cultured distal tubules were treated with high sodium and glucose in the presence of EMPA, LINA, or GLP-1. [4] Urine samples were collected from patients with DM treated with LINA, EMPA, or the combination to investigate urinary sodium excretion.

Results

Tubular injury and renal fibrosis in SDT-fatty rats were improved by EMPA or EMPA + LINA. Along with lowered glucose level, renal dysfunction was attenuated by EMPA or EMPA + LINA. Urinary sodium excretion was increased by combination of the two when compared to EMPA alone. Renal ENaC was reduced with upregulation of Nedd4-2 by EMPA + LINA. Also, combination of the two attenuated hypertension with increase in urinary sodium excretion in DOCA/salt mice. Upregulation of Nedd 4-2 in DOCA/salt mice was prevented by the combination, but not EMPA alone. High sodium and glucose medium increased ENaC expression and suppressed Nedd4-2 expression, both of which were reversed by co-incubation with GLP-1 or LINA. Among the patients with DM, urinary sodium excretion was increased by combination of the two even when compared to EMPA or LINA alone.

Conclusion

LINA can become a potent to prevent the progression of DM-N through deactivating ENaC leading to increased urinary sodium excretion.