Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure
| Autor: | Juliano Z. Polidoro, Aline Cavalcantti T. Wisnivesky, Gerhard Malnic, Flávio A. Borges-Júnior, Ednei Luiz Antonio, Danúbia Silva dos Santos, Acaris Benetti, Bruno Caramelli, Adriana C. C. Girardi, Paulo José Ferreira Tucci, Renato O. Crajoinas, Leonardo Jensen |
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| Rok vydání: | 2021 |
| Předmět: |
IMMUNOBLOTTING
medicine.medical_specialty medicine.drug_class business.industry medicine.medical_treatment Renal function General Medicine medicine.disease Pathophysiology Basic Research Endocrinology Nephrology Heart failure Internal medicine medicine Empagliflozin Natriuretic peptide SGLT2 Inhibitor Diuretic business Saline |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP J Am Soc Nephrol |
| ISSN: | 1533-3450 1046-6673 |
| Popis: | Background SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. Methods Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. Results EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. Conclusions Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF. |
| Databáze: | OpenAIRE |
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