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Empagliflozin Prevents Renal Dysfunction and Inhibits Proximal Tubule NHE3 Activity in Nondiabetic Heart Failure Rats
Author(s) -
Junior Flavio Araujo Borges,
dos Santos Danubia Silva,
Crajoinas Renato Oliveira,
Wisnivesky Aline Cavalcantti T.,
Benetti Acaris,
Rios Thiago Matheus Santos,
Antonio Ednei Luiz,
Tucci Paulo,
Girardi Adriana Castello Costa
Publication year - 2020
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.2020.34.s1.04845
Subject(s) - empagliflozin , empa , medicine , endocrinology , heart failure , renal function , type 2 diabetes , diabetes mellitus , cardiology , chemistry , mineralogy , electron microprobe
Sodium‐glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control by suppressing glucose reuptake in the renal proximal tubule (PT). Primarily designed as antidiabetic agents, these drugs also reduce cardiovascular death and hospitalization for heart failure (HF), regardless of the presence or absence of type 2 diabetes. However, the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors remain unknown. Given the importance of the cardiorenal axis in HF care, this study aimed to test the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) is capable of exerting renoprotective effects in the setting of nondiabetic HF. To this end, male Wistar rats were subjected to ligation of the anterior descending coronary artery or sham operation. Four weeks after surgery, rats were fed normal chow, with or without EMPA, for an additional 4 weeks. Compared with sham‐groups, HF rats treated with EMPA had similar serum BNP levels, whereas cardiac dysfunction deteriorated it further in HF rats (Sham: 0.5 ± 0.1; Sham+EMPA: 0.5 ± 0.1; HF: 2.1 ± 0.3; HF+EMPA: 0.9 ± 0.1 ng/mL). Additionally, HF rats exhibited an increase in lung (Sham: 3.2 ± 1.5; Sham+EMPA: 31.8 ± 1.1; HF: 44.7 ± 3.3; HF+EMPA: 32.7 ± 1.7 mg/mm) and right ventricle (Sham: 6.3 ± 0.2; Sham+EMPA: 5.2 ± 0.2; HF: 8.9 ± 1.0; HF+EMPA: 6.4 ± 0.3 mg/mm) mass. Renal function was impaired in HF rats as evidenced by low glomerular filtration rate (GFR) and high levels of plasma urea and urinary protein excretion. However, EMPA treatment restored these parameters to sham rats levels [(GFR, Sham: 6.5 ± 0.2; Sham+EMPA: 7.7 ± 0.6; HF: 4.5 ± 0.4; HF+EMPA: 7.7 ± 0.4 mL/min/kg) (Plasma urea, Sham: 37 ± 1; Sham+EMPA: 38 ± 2; HF: 48 ± 2; HF+EMPA: 39 ± 1 mg/dL) (Urine protein to creatinine ratio, Sham: 1.2 ± 0.1; Sham+EMPA: 1.0 ± 0.1; HF: 1.8 ± 0.1; HF+EMPA: 1.3 ± 0.1)]. Furthermore, EMPA prevented reduction of hematocrit in HF rats (Sham: 48.7 ± 0.3; Sham+EMPA: 49.5 ± 0.7; HF: 45.8 ± 0.5; HF+EMPA: 49.7 ± 0.4 %). In vivo stationary microperfusion showed that EMPA reduced Na + /H + exchanger isoform 3 (NHE3) activity in HF rats, similar to sham‐groups (Sham: 2.05 ± 0.04; Sham+EMPA: 1.40 ± 0.05; HF: 4.36 ± 0.08; HF+EMPA: 1.54 ± 0.05 nmol/cm 2 ). Collectively, these findings demonstrate that SGLT2 inhibition ameliorates renal dysfunction and improves the volemic status of nondiabetic HF rats. Support or Funding Information Supported by FAPESP and CAPES.