Glucagon like peptide-1 modulates urinary sodium excretion in diabetic kidney disease via ENaC activation

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Glucagon like peptide-1 modulates urinary sodium excretion in diabetic kidney disease via ENaC activation

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Co-author 1

Goh Kodama kodama_gou@kurume-u.ac.jp Kurume university Internal Medicine Kurume Japan *

Co-author 2

Kensei Taguchi taguchi_kensei@kurume-u.ac.jp Kurume university Internal Medicine Kurume Japan -

Co-author 3

Sakuya Ito ito_sakuya@kurume-u.ac.jp Kurume university Internal Medicine Kurume Japan -

Co-author 4

Yuta Mitsuishi mitsuishi_yuta@kurume-u.ac.jp Kurume university Internal Medicine Kurume Japan -

Co-author 5

Yuya Yamashita yamashita_yuya@kurume-u.ac.jp Kurume university Internal Medicine Kurume Japan -

Co-author 6

Kei Fukami fukami@kurume-u.ac.jp Kurume Internal Medicine Kurume Japan -

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Introduction

Diabetic kidney disease (DKD) is a leading cause of end stage kidney disease worldwide. Approximately half of patients with diabetes develop salts-sensitive hypertension, resulting in further progression of kidney injury. Upregulation of epithelial sodium channel (ENaC) is known to be associated with salt-sensitive hypertension in patients with diabetes. While SGLT2is reduce hospitalization for heart failure, their effects on urinary sodium excretion (USE) are minimal or transient. Consequently, adjunct pharmacotherapeutics that, when combined with SGLT2is, enhance USE and improve salt sensitivity remain undefined. In the present study, we investigated whether linagliptin (LINA), a DPP4 inhibitor (DPP4is), coordinates with SGLT2 inhibitor to attenuate DKD and explored the synergetic effect of LINA in diabetic and hypertensive rodents as well as patients with DM.

Methods

(1) SDT-fatty rats on high-salt diet were assigned to sham, DKD, DKD+EMPA (12 weeks), or DKD+EMPA 6 weeks then LINA 6 weeks (EMPA+LINA). (2) DOCAsalt mice (ENaC-activated hypertension) received EMPA or EMPA+LINA. (3) SD rats received i.v. EMPA, i.v. LINA, concurrent i.v. EMPA+LINA, or LINA 1 h after EMPA to compare USE. (4) Cultured distal tubules were exposed to high sodium and glucose with EMPA, LINA, or GLP-1. (5) In our retrospective cohort, USE was compared in DKD patients treated with SGLT2is alone versus SGLT2is+DPP4is.

Results

Tubular injury and renal fibrosis in SDT-fatty rats were improved by EMPA alone or EMPA+LINA. Along with lowered glucose level, renal dysfunction was attenuated by EMPA alone or EMPA+LINA. USE was increased by combination of the two when compared to EMPA alone. Renal ENaC expression was reduced with upregulation of Nedd4-2 by EMPA+LINA. Furthermore, combination of the two attenuated hypertension with increase in USE in DOCAsalt mice. Upregulation of Nedd4-2 was prevented by the combination, but not EMPA alone in DOCAsalt mice. Time lagged injection of LINA after EMPA sustained USE compared with concomitant injection of the two. 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, USE was increased by combination of the two even when compared to EMPA or LINA alone.

Conclusion

GLP-1 modulates USE in DKD via ENaC activation and improves salt sensitivity, which leads to attenuation DKD.

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