K TRINH 1, S JULOVI 1, N MINHAS 1, J LI 1, K GHIMIRE 1, N ROGERS 1,2
1The Westmead Institute For Medical Research, Westmead, Australia, 2Westmead Hospital, Westmead, Australia
Background and Aims: Patients with chronic kidney disease (CKD) are at significantly greater risk of cardiovascular disease, which manifests as cardiorenal syndrome (CRS) and remains the leading cause of mortality. Clinical trials targeting standard cardiovascular risk factors fail to improve outcomes in CKD patients. The cell-surface receptor CD47 regulates cell responses to stress and we investigated its role in CRS.
Method: Age-matched male C57BL/6 (WT) and CD47KO mice were subjected to a 5/6 nephrectomy model (5/6-Nx) of CRS. Blood pressure and weight were checked weekly. At 12 weeks, we performed echocardiography followed by biomolecular phenotyping on tissues. Human cardiomyocytes were used to assess the effect of CD47 blockade on proliferation and senescence.
Results: After 12 weeks, WT 5/6-Nx mice developed renal fibrosis, hypertension, and left ventricular hypertrophy (LVH) with increased ejection fraction compared to baseline. Histologic examination of myocardium revealed interstitial and perivascular fibrosis, as well as upregulated myocardial CD47 expression. These findings were mitigated in CD47KO mice with preserved LV function, reduced LVH and cardiac fibrosis despite equivalent changes in renal mass and blood pressure. mRNA levels of cardiac-based TNF-α, IL-6, collagen, fibronectin and α-smooth muscle actin were increased in WT mice compared to sham-operated controls and CD47KO 5/6-Nx mice. Injection of the uremic toxin indoxyl sulfate into WT mice caused LVH, which was reduced in the presence of αCD47 antibody. In vitro, cardiomyocyte senescence (β-galactosidase staining, pro-inflammatory cytokine production) and hypertrophy was induced by indoxyl sulfate but mitigated by blocking CD47. This effect was dependent upon activation of the aryl hydrocarbon receptor.
Conclusion: Manipulation of CD47 signalling is an attractive target to reduce the excessive burden of CRS in CKD.
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