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Empagliflozin Inhibits NHE3 Activity in the Proximal Tubule of Normotensive and Hypertensive Rats
Author(s) -
Borges Flávio Araújo,
Silva Corina Albuquerque,
Crajoinas Renato Oliveira,
CasteloBranco Regiane Cardoso,
Luchi Weverton Machado,
Girardi Adriana Castello Costa
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb355
Subject(s) - empagliflozin , medicine , endocrinology , reabsorption , blood pressure , chemistry , kidney , type 2 diabetes , diabetes mellitus
Background A growing body of evidence suggests an interplay between extracellular volume and glucose homeostasis. NHE3 is the main pathway for Na reabsorption in the proximal tubule (PT). The sodium glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys and colocalizes with NHE3 in the apical membrane of PT. Thus, we tested the hypothesis that SGLT2 and NHE3 functionally interact. Given that SGLT2 inhibitors confer blood‐pressure lowering effects in T2DM patients, we also tested the hypothesis that the antihypertensive effects of SGLT2 inhibitors may be associated with PT NHE3 inhibition. Methods The acute and long‐term effects of the SGLT2 inhibitor empagliflozin on PT NHE3 activity were determined by in vivo stationary microperfusion in fourteen‐week‐old male Wistar rats and SHR‐treated rats. Additionally, twelve‐week‐old SHRs were treated with empagliflozin (10 mg/kg/day) or vehicle (control) for two weeks. Tail‐cuff blood pressure and renal function were measured before (baseline) and after treatment (post‐treatment). NHE3 expression and phosphorylation levels were evaluated by immunoblotting. Results Empagliflozin acutely inhibited PT NHE3 activity in both Wistar (1.73 ± 0.07 vs. 2.55 ± 0.14 nmol/cm 2 .s, P < 0.001) and SHR (0.82 ± 0.07 vs. 1.21 ± 0.10 nmol/cm 2 .s, P < 0.01). Blood pressure (BP) of empagliflozin‐treated SHR was lower than baseline levels (176 ± 4 vs. 194 ± 4 mm Hg, P < 0.01) whereas no change in BP was observed in vehicle‐treated SHR (194 ± 6 vs. 192 ± 5 mm Hg). Compared to baseline, empagliflozin‐treatment enhanced cumulative urinary flow, calcium, sodium and glucose excretion whereas in vehicle‐treated SHR these parameters remained unchanged. Lower BP in empagliflozin‐treated SHR was associated with lower PT NHE3 activity (0.67 ± 0.10 vs. 1.18 ± 0.10 nmol/cm 2 .s, P < 0.001). No differences were observed on renal cortical NHE3 protein expression or NHE3 phosphorylation levels between the two groups of rats. Conclusion These results suggest that NHE3 and SGLT2 functionally interact in the PT. Inhibition of NHE3 by SGLT2 inhibitors may underlie, at least in part, the antihypertensive effect of empagliflozin. Support or Funding Information FAPESP This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .