Inhibition of neprilysin with sacubitril without RAS blockage aggravates renal disease in Dahl SS rats.

Abstract:

:Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from salt retention is associated with counterintuitively lower levels of atrial natriuretic peptide (ANP). In plasma, ANP is degraded by the neprilysin; therefore, pharmacological inhibition of this metalloprotease (i.e., with sacubitril) can be employed to increase ANP level. We have shown earlier that sacubitril in combination with valsartan (75 μg/day each) had beneficial effects on renal function in Dahl SS rats. The goal of this study was to evaluate the effects of a higher dose of sacubitril on renal damage in this model. To induce hypertension, male Dahl SS rats were fed a 4% NaCl diet (HS) for 21 days, and were administered sacubitril (125 μg/day) or vehicle via s.c. osmotic pumps. At the end of the HS challenge, both groups exhibited similar outcomes for GFR, heart weight, plasma electrolytes, BUN, and creatinine. Sacubitril exacerbated kidney hypertrophy, but did not affect levels of renal fibrosis. We also observed aggravated glomerular lesions and increased formation of protein casts in the sacubitril-treated animals compared to controls. Thus, in Dahl SS rats, administration of sacubitril without renin-angiotensin-system blockage had adverse effects on renal disease progression, particularly in regards to glomerular damage and protein cast formation. We can speculate that while ANP levels are increased because of neprilysin inhibition, there are off-target effects of sacubitril, which are detrimental to renal function in the SS hypertensive state.

journal_name

Ren Fail

journal_title

Renal failure

authors

Polina I,Spicer MJ,Domondon M,Schibalski RS,Sarsenova E,Sultanova RF,Ilatovskaya DV

doi

10.1080/0886022X.2021.1879856

keywords:

["Sacubitril","hypertension","kidney","neprilysin","salt-sensitivity"]

subject

Has Abstract

pub_date

2021-12-01 00:00:00

pages

315-324

issue

1

eissn

0886-022X

issn

1525-6049

journal_volume

43

pub_type

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