Cardiac LIM Protein, Kidney Fibrosis, and Vascular Change after Acute Cardiorenal Syndrome

Abstract

Key Points:

1. CKD caused after acute cardiorenal syndrome is distinct from CKD due to kidney injury from the ischemia-reperfusion injury model.

2. A cardiac-specific protein, cysteine-and-glycine–rich protein 3, transits plasma after heart injury and is partially responsible for distinct CKD.

3. The cardiac-specific protein, cysteine-and-glycine–rich protein 3, is taken up in the proximal tubular epithelial cells, and interference with this uptake prevents specific changes.

Background: The heart and kidney are bidirectionally interacting organs. Because heart and kidney diseases are among the most common human diseases, investigating disease-causing interactions is important. Here, we identified a new role for cardiac-derived cardiac LIM protein, also known as cysteine-and-glycine–rich protein 3 (CSRP3), in acute cardiorenal syndrome.

Methods: Mice, both wild-type and genetically altered to remove CSRP3 from the myocardium, were subjected to a model of acute cardiorenal syndrome, cardiac arrest and cardiopulmonary resuscitation (CA/CPR), or ischemia-reperfusion injury. Recombinant CSRP3 was administered to mice subjected to ischemia-reperfusion injury, and CSRP3 uptake in the kidney was inhibited by pharmacologic means.

Results: We found that CSRP3 transits plasma after CA/CPR, and we determined a kidney disease–modifying mechanism in which CSRP3 underwent megalin-dependent endocytosis in the renal proximal tubule and subsequently drove kidney fibrosis. Administration of CSRP3 to mice experiencing kidney injury exclusive of heart injury reproduced the kidney phenotype observed in CA/CPR mice. Genetic deletion of cardiac CSRP3 or proximal tubule megalin ameliorated cardiac arrest–induced chronic kidney injury. Translationally relevant pharmacologic megalin inhibition also ameliorated CSRP3-mediated kidney phenotypic change, and administration of CSRP3 caused transcriptional change in the kidney.

Conclusions: We describe the endocrine role of cardiac CSRP3 in a previously unknown heart–kidney interaction, which directs specific kidney dysfunction and renovascular remodeling after cardiac injury. These investigations elucidate a novel facet of the intricate coupling between the heart and kidney after acute cardiorenal syndrome.

Trial registration: ClinicalTrials.gov NCT03595189.

Keywords: CKD; cardiovascular events; cell and transport physiology; endocytosis; hypertension and cardiorenal disorders.