Thrombospondin-1 Drives Cardiac Remodeling in Chronic Kidney Disease

Sohel M Julovi; Katie Trinh; Harry Robertson; Cuicui Xu; Nikita Minhas; Seethalakshmi Viswanathan; Ellis Patrick; John D Horowitz; Daniel N Meijles; Natasha M Rogers

doi:10.1016/j.jacbts.2024.01.010

Thrombospondin-1 Drives Cardiac Remodeling in Chronic Kidney Disease

JACC Basic Transl Sci. 2024 Mar 27;9(5):607-627. doi: 10.1016/j.jacbts.2024.01.010. eCollection 2024 May.

Authors

Sohel M Julovi^{1

2}, Katie Trinh¹, Harry Robertson^{1

2

3}, Cuicui Xu¹, Nikita Minhas¹, Seethalakshmi Viswanathan^{2

4}, Ellis Patrick^{1

3

5

6}, John D Horowitz^{7

8

9}, Daniel N Meijles⁷, Natasha M Rogers^{1

2

10}

Affiliations

¹ Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
² Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.
³ Sydney Precision Data Science Centre, University of Sydney, New South Wales, Australia.
⁴ Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia.
⁵ School of Mathematics, University of Sydney, New South Wales, Australia.
⁶ Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong Special Administrative Region, China.
⁷ Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom.
⁸ Cardiovascular Pathophysiology and Therapeutics Research Group, Basil Hetzel Institute, Woodville, South Australia, Australia.
⁹ Department of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
¹⁰ Renal and Transplantation Unit, Westmead Hospital, New South Wales, Australia.

Abstract

Patients with chronic kidney disease (CKD) face a high risk of cardiovascular disease. Previous studies reported that endogenous thrombospondin 1 (TSP1) involves right ventricular remodeling and dysfunction. Here we show that a murine model of CKD increased myocardial TSP1 expression and produced left ventricular hypertrophy, fibrosis, and dysfunction. TSP1 knockout mice were protected from these features. In vitro, indoxyl sulfate is driving deleterious changes in cardiomyocyte through the TSP1. In patients with CKD, TSP1 and aryl hydrocarbon receptor were both differentially expressed in the myocardium. Our findings summon large clinical studies to confirm the translational role of TSP1 in patients with CKD.

Keywords: aryl hydrocarbon receptor; cardiac fibrosis; chronic kidney disease; left ventricular hypertrophy; thrombospondin 1.