THROMBOSPONDIN-1 IS A NOVEL TARGET DRIVING TYPE 4 CARDIORENAL SYNDROME.
Natasha Rogers1, Katie Trinh1, Cuicui Xu1, Sohel Julovi1 1Westmead Institute for Medical Research, Westmead, NSW, Australia
Abstract
Background:and Aims:
Patients with chronic kidney disease (CKD) are at significantly greater risk of cardiovascular disease (CVD), which remains the leading cause of hospitalisation and mortality. Clinical trials targeting standard cardiovascular risk factors fail to improve outcomes in CKD patients, leading to analysis of non-traditional pathways. The protein thrombospondin-1 (TSP1) regulates cell responses, and we investigated its role in CVD.
Method: Age-matched male C57BL/6 (WT) and TSP1KO mice were subjected to a 5/6 nephrectomy model (5/6Nx) of CKD. Blood pressure and weight were checked weekly, and echocardiography and molecular phenotyping was performed at 12 weeks. A separate cohort of WT mice received TSP1 blocking antibody fortnightly. Human cardiomyocytes were used to assess the effect of TSP1 on cell function.
Results: WT 5/6Nx mice developed renal fibrosis and concurrent left ventricular (LV) hypertrophy with preserved ejection fraction compared to baseline. Histologic examination of myocardium revealed interstitial and perivascular fibrosis and myocardial TSP1 expression. These findings were mitigated in TSP1KO mice with unchanged LV function, reduced LV hypertrophy and limited cardiac fibrosis despite equivalent changes in renal mass and blood pressure. Cardiac mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6) and fibrosis markers (collagen, fibronectin and α-smooth muscle actin) were increased in WT compared to both TSP1KO 5/6Nx mice and WT mice treated with anti-TSP1 antibody. In vitro, TSP1 promoted a senescence-associated secretory phenotype, and this was dependent upon activation of the aryl hydrocarbon receptor. Pre-incubation with a TSP1-blocking antibody or siRNA reversed these effects.
Conclusion: TSP1 is upregulated in CKD and may drive the cardiovascular manifestations of uremia. Manipulating TSP1 signalling is an attractive target to reduce the excessive burden of CVD in CKD patients.
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