The effects of low dose LCZ 696 on kidney function in Dahl SS rats
Authors: Domondon Mark , Polina Iuliia , Fomin Mikhail , Fox Rebecca , Sudarikova Anastasia , Ilatovskaya Daria 
Published: April 2020

Recent reports and our data showed that increasing circulating Atrial Natriuretic Peptide (ANP) levels could be beneficial for attenuating renal disease progression. ANP is a hormone that is known to stimulate salt excretion and vasodilation, thus reducing the blood pressure (BP). Recently, a new drug (LCZ 696, also known as Entresto) was approved by FDA to be used in heart failure; LCZ 696 is a combination of a neprilysin inhibitor (sacubitril), which increases ANP levels, and a known RAAS blocker (valsartan). The goal of this project was to test a low dose of LCZ 696 can be beneficial for the mitigation of renal damage is salt‐sensitive (SS) hypertension.

LCZ 696 (sacubitril and/or valsartan) was administered chronically at 75 ug/day to a model of SS hypertension, Dahl SS rats, via an osmotic pump. Animals were fed a 0.4% NaCl (normal salt, NS) diet until 8 weeks of age, and then underwent a high salt (HS) 4% NaCl challenge for 21 days. Vehicle (veh), sacubitril (sac), valsartan (val), or a 1:1 mix of both drugs (sac/val, or LCZ 696) were administered together with the HS diet; metabolic cage studies and GFR measurements were performed. Collection of the renal tissue, blood plasma and urine allowed for examination of electrolyte excretion, glomerular damage, renal damage markers, proteinuria, as well as protein cast and fibrosis formation.

Post HS challenge, the endpoint kidney‐to‐body‐weight ratio (indicative of hypertrophy) was similar between groups. Urine flow was elevated in all the HS diet fed groups compared to the NS diet (p<0.001 for all); a trend for a lower urine output as well as water consumption was observed in the sac‐treated group. Urinary electrolyte analysis after 21 days on HS diet showed significant increases for Na+ (0.28±0.04 to 1.12±0.12 mM/day/100g, 0.23±0.02 to 1.26±0.12 mM/day/100g, 0.27±0.02 to 1.21±0.14 mM/day/100g, 0.30±0.03 to 1.29±0.08 mM/day/100g for veh, s/v, sac, and val groups respectively). Cl− excretion increased among all groups in a similar manner. After the HS challenge, GFR decreased in the veh group, and increased in the sac/val and sac groups (this increase was attenuated in the val group). Glomerular damage scoring of Masson trichrome stained slides revealed a pattern for lower damage in the val group. Interestingly, proteinuria was less pronounced in the sac/val and val groups (vs control). In addition, we observed an increase in urinary KIM‐1 and NGAL excretion in the control and sac animals, which was attenuated in the sac/val and val groups. Protein cast formation was also lower in the sac/val and val groups after the HS diet compared to the veh group (s/v: p=0.00331, val: p=0.0228).

Our data show attenuation of the SS hypertension progression in the sac/val (LCZ 696) and val treated groups; future studies will be devoted to establishing the effects of a higher dose of LCZ 696 for the alleviation of renal damage and hypertension.

Support or Funding Information

This study was supported by: the National Institutes of Health (NIDDK) R00 DK105160, Dialysis Clinic Inc Reserve Fund, the MUSC SCTR support program via NIH/NCATS UL1TR001450, and the APS Lazaro J Mandel award (to DVI).