ACEI plus GLP1-RA or SGLT2i, as well as ARNI, exerted distinct protective effects against diabetic nephropathy and heart failure with preserved ejection fraction in eNOS-/- dbdb mice
K K Yu, W WangAbstract
Introduction
Whether the loss of endothelial nitric oxide synthase (eNOS) in a diabetic setting leads to cardiac dysfunctions are not completely understood, needless to say a comprehensive evaluation of drugs treating heart failure and diabetes. Our study revealed severe diabetic nephropathy, heart failure with preserved ejection fraction (HFpEF) and cardiac hypertrophy and fibrosis in eNOS-/- dbdb mice. Treatment with ACEI plus GLP1-RA or SGLT2i, or ARNI alone not only restored cardiac diastolic function but ameliorated associated cardio-renal impairments to varying degrees.
Purpose
To systematically characterize the cardio-renal dysfunctions in eNOS-/- dbdb mice with a comprehensive evaluation of ACEI+GLP1-RA, ACEI+SGLT2i or ARNI monotherapy.
Methods
Lisinopril (ACEI) plus semaglutide (GLP1-RA) or dapagliflozin (SGLT2i) or LCZ696 (ARNI) monotherapy were used to treat WT and eNOS-/- dbdb mice for 8 weeks or 4 weeks respectively at the age of 10 or 14 weeks old. Body weight, blood glucose was monitored weekly and blood pressure was checked via tail-cuff system after treatment of ACEI plus GLP1-RA or SGLT2i for 4 weeks. Glomerular filtration rate (GFR) test, HE and PAS stainings were used to assess the renal functions while Echocardiogram, HE, HW/tibia length and PSR stainings were used to evaluate the cardiac dysfunction, hypertrophy and pathological changes including necrosis, thrombus and fibrosis. Serum makers including IL-18, TNF-alpha and GDF15 were tested via ELISA.
Results
Around threefold increase in blood glucose, two fold increase in body weight, a 20 mmHg increase in blood pressure and halved GFR as well as doubled PAS positive staining in kidney were observed in the eNOS-/- dbdb mice. Echocardiographic analysis revealed that the mice exhibited cardiac dysfunction and hypertrophy with IVRT and LVWTs elevated by twofold and 50%, respectively. Concurrently, a 50% increase was detected in the HW/TL and picrosirius red (PSR) staining of cardiac fiborsis, alongside histopathological abnormalities including myocardial atrophy, necrosis and thrombosis. Treatment with ACEI plus GLP1-RA or SGLT2i, or ARNI alone all restored cardiac diastolic function. While ACEI plus GLP1-RA or SGLT2i also improved kidney dysfunction in GFR test and PAS staining, SGLT2i distinctively reduced the blood glucose level, GLR1-RA reduced the body weight and cardiac hypertrophy. ARNI alone fully restored the cardiac hypertrophy and fibrosis as well as alleviate the histopathological malformations in heart sections. Serum IL-18, GDF15 as well TNF-alpha in eNOS-/- dbdb mice elevated while the treatment with ACEI plus GLP1-RA or SGLT2i, or ARNI alone reduced those levels to varying degrees.
Conclusion
Combination therapy with ACEI plus GLP1-RA or SGLT2i, as well as monotherapy with ARNI can alleviate DN and HFpEF phenotypes, particularly on the rescue of impaired cardiac diastolic function and the improvement of other cardio-renal dysfunctions.