Dr KATIE TRINH1,2, Dr CUICUI XU1, JOSEPHINE CHAO1, Dr SOHEL JULOVI1,2, Professor NATASHA M ROGERS1,2,3
1Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia, 2Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia, 3Renal and Transplantation Medicine, Westmead Hospital, Westmead , Australia
Biography:
Dr Katie Trinh is a PhD candidate at the Westmead Institute for Medical Research through the University of Sydney and Staff Specialist Nephrologist at Blacktown and Mount Druitt Hospitals. Her research focuses on the role of TSP1-CD47 signalling in the pathophysiology of cardiovascular disease in chronic kidney disease. She is supervised by Professor Natasha Rogers and Dr Sohel Julovi.
Background:
Cardiovascular disease (CVD) remains a leading cause of death in patients with chronic kidney disease (CKD). Angiotensin-converting enzyme inhibitors (ACEi), the standard of care in CKD, confer some cardioprotection. We recently identified that the extracellular matrix protein thrombospondin-1 (TSP1) is elevated in CKD and is a key mediator of CKD-driven cardiac remodelling. Recent reports suggest that ACEi increases expression of TSP1 in hypertensive patients.
Aim:
To compare the efficacy of a TSP1-binding antibody (αTSP1Ab) and ACEi lisinopril in a preclinical model of CKD-induced cardiac remodelling.
Methods:
CKD was induced in male C57BL/6 mice by 5/6 nephrectomy (5/6Nx). CKD mice received either ⍺TSP1Ab or isotype IgG (25μg/g, intraperitoneally, fortnightly for 5 doses), or lisinopril (20mg/kg/day by oral gavage) for 10 weeks. At week 12, CKD parameters and cardiovascular pathology were assessed using biomarkers, histology, echocardiography and molecular analysis.
Results:
The 5/6Nx model effectively reproduced CKD and associated cardiac complications, including left ventricular hypertrophy, myocardial fibrosis, pulmonary congestion, senescence-associated secretory phenotype, and calcium-phosphate imbalance. Both αTSP1Ab and lisinopril significantly attenuated these pathologies by reducing cardiac oxidative stress, pro-inflammatory cytokine profile, and cellular senescence (p53 expression). Notably, lisinopril also suppressed CKD-induced TSP1 expression in the heart. αTSP1Ab – but not lisinopril – mitigated cardiac fibrosis. Antibody treatment produced marked functional cardiac improvements, with reduced heart weight and increased cardiac output, as well as restoration of posterior wall thickness and diastolic volumes.
Conclusion:
αTSP1Ab substantially mitigates cardiac pathology in CKD, and TSP1 may contribute to the cardioprotective effects of lisinopril.