Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench.
Am J Physiol Cell Physiol
; 325(3): C661-C681, 2023 09 01.
Article
em En
| MEDLINE
| ID: mdl-37519230
ABSTRACT
Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Insuficiência Renal Crônica
/
Inibidores do Transportador 2 de Sódio-Glicose
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article