Identifying pathways that promote cardiovascular pathology in chronic kidney disease

Abstract

Individuals with chronic kidney disease (CKD) have a high risk of cardiovascular (CV) morbidity and mortality, for which there are limited treatment options. Uraemic toxins, such as indoxyl sulfate (IS), are a non-traditional CV risk factor. Enhanced understanding of the underlying molecular mechanisms will provide new pharmacological targets. This thesis explores the role of the cell stress response protein, thrombospondin-1 (TSP1) and its receptor CD47 in the development of uraemic cardiomyopathy and CKD-associated vascular remodelling.

Wild-type (WT) C57BL/6 mice with CKD induced by 5/6 nephrectomy (5/6Nx) had upregulated myocardial TSP1 expression and developed features of uraemic cardiomyopathy: left ventricular (LV) hypertrophy (LVH), cardiac fibrosis and LV diastolic dysfunction. This was associated with senescence-associated secretory phenotype, enhanced mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and aryl hydrocarbon receptor (AhR) signalling. These were mitigated in TSP1 knockout (KO) 5/6Nx mice. In vitro, the pathological effects of IS on human cardiomyocytes required intact TSP1 signalling. Furthermore, 5/6Nx mice treated with anti-TSP1 monoclonal antibody were protected against cardiac remodelling, suggesting TSP1 blockade as a potential therapeutic tool.

CD47KO-5/6Nx mice showed preserved aortic adventitial wall thickness and limited expression of senescence marker, p53, compared to WT-5/6Nx mice. In vitro, IS and exogenous TSP1 increased TSP1 expression in human aortic vascular smooth muscle cells, reduced cell proliferation, elevated β-galactosidase activity and enhanced MAPK/ERK and AhR signalling, which were attenuated by CD47 blockade.

This thesis provides novel insights into the role of TSP1–CD47 signalling in the development of uraemic cardiomyopathy and vascular remodelling in CKD. Interruption of TSP1- and/or CD47-signalling may represent a novel therapeutic strategy to mitigate CV complications in CKD.