N ROGERS1, S JULOVI1, K GHIMIRE1, N MINHAS1
1Westmead Institute for Medical Research, Westmead, Australia
Background: Patients with chronic kidney disease (CKD) are at significantly greater risk of cardiovascular disease (CVD), which remains the leading cause of death. Targeting standard cardiovascular risks fails to improve outcomes in CKD patients, suggesting that non-traditional pathways drive development of CVD. We recently identified a role for the protein thrombospondin-1 (TSP1) in CKD, and we now investigate its role in cardiac pathology.
Method: Plasma was collected from CKD patients and TSP1 measured by ELISA. Age-matched male C57BL/6 (WT) and TSP1KO mice underwent 5/6 nephrectomy (5/6-Nx). Blood pressure, weight and cardiac function were analysed at baseline and 12 weeks.
Results: Linear regression analysis demonstrated that human plasma TSP1 correlated inversely with eGFR (p<0.001). WT-5/6-Nx mice developed renal fibrosis and hypertension at 12 weeks, in addition to elevated plasma TSP1. Left ventricular (LV) hypertrophy and diastolic dysfunction was confirmed by echocardiography. Histologic examination of WT myocardium revealed fibrosis and increased TSP1 expression. These findings were mitigated in TSP1KO mice who demonstrated preserved LV function, minimal LV hypertrophy and cardiac fibrosis with equivalent changes in renal mass and blood pressure. mRNA levels of cardiac-based TNF-α, IL-6, collagen and fibronectin were increased in WT 5/6-Nx mice compared to sham-operated and TSP1KO-5/6-Nx mice. In vitro, the addition of uremic toxin indoxyl sulfate to cardiomyocytes induced hypertrophy and upregulated TSP1 expression. Indoxyl sulfate significantly down-regulated cardiomyocte proliferation and increased β-galactosidase activity (senescence), which were reversed by pre-incubation with either a TSP1-blocking antibody or TSP1 siRNA.
Conclusion: Our findings show that TSP1 is elevated in CKD and drives cardiovascular manifestations of uraemia. Manipulating TSP1 signalling is an attractive target to potentially reduce the excessive burden of CVD in CKD patients.
Associate Professor Natasha Rogers is a Transplant Nephrologist, Senior Staff Specialist and Head of the Clinical Islet Transplant Program at Westmead Hospital. She is also an adjunct Assistant Professor at the Starzl Transplant Institute in Pittsburgh Pennsylvania, current Deputy Chair of SPEC (ANZSN) and Secretary of TSANZ. A/Prof Rogers is currently a NHMRC Career Development Fellow at the University of Sydney and runs the Kidney Injury Group at the Westmead Institute for Medical Research. She has been awarded >$3million in competitive funding, focusing on the molecular mechanisms of acute and chronic kidney injury.