A heart derived-soluble factor which controls kidney and cardiovascular function after acute cardiorenal syndrome

Abstract Heart and kidney are bi-directionally interacting organs. Because heart and kidney disease are amongst the most common human diseases, investigating disease-causing interactions is important. Here, we identified a new heart-derived endocrine mediator of kidney function, cardiac cysteine-and-glycine-rich protein 3 (CSRP3). We determined CSRP3's stimulus for release from the heart, plasma transit, and kidney disease-causing mechanism. We found that cardiac CSRP3 was upregulated after cardiac injury (modeled using cardiac arrest and cardiopulmonary resuscitation in the mouse), and released into the systemic circulation, subsequently undergoing megalin-dependent endocytosis in the renal proximal tubule and changing kidney cell phenotype. Administration of CSRP3 to mice experiencing focal kidney injury reproduced the kidney phenotype observed in cardiac arrest-exposed mice. Genetic deletion of cardiac CSRP3 or renal megalin ameliorated cardiac injury-induced chronic kidney injury. Lastly, pharmacologic megalin inhibition ameliorated CSRP3-mediated chronic renal injury. We describe the role of cardiac CSRP3 in a heart-kidney interaction which directs specific renal dysfunction and renovascular remodeling after injury. We describe a novel mechanism of the intricate coupling of heart and kidney which determines renal function. These investigations may eventually lead to novel therapy for heart-induced kidney disease.