Differential effects of low-dose sacubitril and/or valsartan on renal disease in salt-sensitive hypertension

Abstract

Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.

NOX4‐dependent regulation of ENaC in hypertension and diabetic kidney disease

“…Figure 1 illustrates that the HS diet increases urinary volume and sodium excretion similarly to earlier reports. 34,35 HS diet and associated hypertension led to renal damage, which can be detected by elevated albuminuria. As shown in Figure 1B,C SS Nox4−/− rats demonstrated increased daily diuresis and natriuresis on day 3 of dietary intervention indicating improved pressure-natriuretic response at an early stage.…”

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

“…In our study, though BP was not significantly higher, we observed exacerbated renal hypertrophy in the SCB group, which commonly accompanies hypertension [ 60 , 61 ], and is caused in part by microvascular barotrauma [ 62 ]. In our previous study [ 43 ] with a lower dose of sacubitril, we reported no changes in kidney to body weight ratio in the SCB group. We can speculate that when sacubitril dosage is increased, in the absence of ARBs, sacubitril treatment results in increased RAS activation due to the side effects of neprilysin inhibition [ 33 ]; however, more extensive mechanistic studies are required to make definite conclusions.…”

“…Body weight was measured in both groups before the start of the HS challenge (on the NS diet) and after 21 days on the HS diet. Here, we chose to use the 125 μg/day dose of sacubitril (compared to 75 μg/day used by us previously [ 43 ], an average of ∼0.4 mg/kg/day was administered to rats throughout the protocol. For human patients, recommended starting oral dose of a combination drug (Entresto ® ) is 25–50 mg/twice a day (0.7–1.5 mg/kg/day for a 70 kg person).…”

“…Despite differences in sacubitril dosing between this and our previous study, there are some similarities. When comparing protein cast formation with proteinuria-related data from our prior work [ 43 ], it is apparent that sacubitril alone does not attenuate protein casting at either dose. Concerning glomerular damage, we observed a significantly higher glomerular injury score (1.6 a.u.)…”

“…The current study focused on the effects of NEPi monotherapy on renal function of SS hypertension. We initially hypothesized, based on our prior data [ 43 ], that an increase in sacubitril dosage (from 75 μg/day used previously, to 125 μg/day) would enhance the mild beneficial effects of the drug that we observed at a lower dose. The rationale for testing sacubitril monotherapy stemmed from the fact that the RAS is suppressed in the Dahl SS rat [ 18 , 19 ]; based on this, we speculated that a combination therapy with an ARB might not be required for the SS condition.…”