Abstract 16728: LCZ696 Ameliorates Inflammation, Oxidative Stress and Prevents Disease Progression in a Rat Model of Chronic Kidney Disease
Introduction: Chronic kidney disease (CKD) is associated with significant cardiovascular morbidity and mortality. LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor (the latter increases natriuretic peptides (NPs) levels) is a promising new agent which has shown significant potential in treatment of chronic heart failure with reduced ejection fraction. NPs augmentation can not only enhance the antihypertensive impact of RAAS blockade by stimulating vasodilation and natriuresis, it also has antioxidant and anti-inflammatory properties. Furthermore NPs can play a role in restoration of the CKD-related dysfunctional NO pathway. Therefore, we hypothesized that treatment of CKD with LCZ696 will lead to significantly better renal outcomes than angiotensin receptor blockade (ARB) alone.
Methods: Male Sprague Dawley rats underwent sham surgery (n=6) or 5/6 nephrectomy and after two weeks the CKD animals (n=8-12 in each group) were randomized to no treatment (CKD), valsartan (30 mg/kg) (VAL), or LCZ696 (60 mg/kg) (LCZ) by gavage. After 8 weeks, the animals were sacrificed and serum and urine markers of kidney function, renal histology, inflammation and oxidative stress were evaluated.
Results: The untreated CKD rats exhibited elevated serum creatinine, proteinuria and increased tubulointerstitial (TI) injury. In addition, there was upregulation of the pro-inflammatory molecule MCP1 and down-regulation of endothelial nitric oxide synthase (eNOS) and catalase. LCZ696 administration significantly reduced proteinuria, serum creatinine and renal TI injury. Furthermore, LCZ696 treatment decreased renal protein abundance of MCP-1, induced eNOS and increased catalase.
Conclusion: LCZ696 is more effective in preventing progression of renal disease when compared to ARB therapy alone. Further laboratory and clinical studies are needed to explore the potential utility of this novel and promising agent in patients with CKD.
Author Disclosures: W. Jing: None. A. Nunes: None. M. Khazaeli: None. Y. Suematsu: None. S. Farzaneh: None. N. Vaziri: None. H. Moradi: None.
- © 2016 by American Heart Association, Inc.