297. The Influence of ELABELA AAV Gene Therapy on Cardiorenal Function in Rat Models of Salt-Induced Hypertension and Myocardial Infarction

Abstract

Elabela (ELA) is a recently identified apelin receptor agonist essential for cardiac development, but its biology and therapeutic potential are unclear. The apelin receptor when bound to its original ligand, apelin, exerts peripheral vasodilatory and positive inotropic effects. We initially assessed endogenous ELA expression in normal and diseased rats. ELA was predominantly expressed in kidneys, especially in renal collecting duct cells and was not affected by disease. We then characterized the effects of long-term, adeno-associated virus (AAV)-ELA gene delivery on cardiorenal function in Dahl salt-sensitive rats (DS) on a high-salt diet. We overexpressed codon optimized rat ELA in the heart via AAV9 vector by a single intravenous injection. This led to a delayed onset of blood pressure (BP) elevation, and ELA-treated rats had lower BP than controls starting at 5 weeks post-injection (p.i.). As well, ELA significantly reduced fractional sodium and chloride excretion in treated (4 days p.i.), normotensive DS rats on low-salt diet, suggesting ELA's role in sodium and chloride readsorption. Glomerular architecture was better preserved in rats treated with the AAV9-ELA vector. A decrease in renal fibrosis and the significantly suppressed expression of fibrosis associated genes, including transforming growth factor beta (TGF-β), collagen, type 1, alpha 1 (COL1A1) and fibronectin 1 (FN1), was also seen in the treated group. Since ELA is essential for cardiac development, we additionally assessed the impact of the AAV9-ELA vector on cardiac repair in a rat myocardial infarction (MI) model. When compared with control MI rats, ELA treatment did not significantly improve cardiac function or structure. Thus, long-term ELA gene delivery may offer a potential therapy for hypertension and renal remodeling, but its application for MI may be limited.