Linagliptin increases urinary sodium excretion via deactivating renal ENaC in diabetic rodents and patients with diabetes mellites

E-Poster

https://storage.unitedwebnetwork.com/files/1099/46adbe4a7bcc1cf7bc78fab70cc8c38d.pdf

Abstract Title

First Name *

Kensei

Last Name *

Taguchi

Co-author 1

Go Kodama kodama_go@kurume-u.ac.jp Kurume University School of Medicine Division of Nephrology Kurume

Co-author 2

Kei Fukami Fukami@kurume-u.ac.jp Kurume University School of Medicine Division of Nephrology Kurume

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Introduction

About half of patients with diabetes mellitus (DM) develop hypertension, leading to further organ damage. Whereas SGLT2 inhibitors have drawn attention to their renoprotective effects, the glucose-lowering effect is insufficient; thus, additional anti-diabetic agents are required to acquire therapeutic goal of glucose control. Also, the effect of sodium excretion by SGLT2 inhibitors is transient. Thus, it would be of importance of finding a therapeutic agent which can help lower glucose level and promote urinary sodium excretion. 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 diet 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.

Conclusions

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

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