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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.

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.

Salt-sensitive (SS) hypertension is accompanied with severe cardiorenal complications. In this condition, elevated blood pressure (BP) resulting from high salt intake can be partially associated with a lower level of the atrial natriuretic peptide (ANP). In plasma, ANP is quickly degraded by neprilysin; therefore, pharmacological inhibition of this metalloprotease (f.i. with sacubitril) can increase ANP level. We have shown earlier that lower dose of sacubitril in combination with valsartan (75 μg/day) has beneficial effects on renal function in SS hypertension. The goal of this study was to evaluate the effects of sacubitril administered at a higher dose on renal damage of Dahl SS rats. Sacubitril (125 μg/day) or vehicle were administered to male Dahl SS rats (Charles River) via s.c. osmotic pumps. To induce hypertension, both groups were fed a purified 4% NaCl diet (HS, Dyets Inc) for 21 days. Glomerular filtration rate (GFR, FITC-inulin) and BP (tail cuff) values were obtained before and after the HS challenge. Data was analyzed with 1-way ANOVA. When compared to vehicle treated rats, 125 μg/day of sacubitril insignificantly increased systolic BP measured at the end of the 21-day HS challenge; no changes in GFR, heart weight, plasma electrolytes, BUN and creatinine were observed. However, sacubitril caused kidney hypertrophy (two kidneys to body weight: 8.8±0.4 vs 10.4±0.4 mg/g, p=0.04,), but did not affect renal medullary of cortical fibrosis. We also observed aggravated glomerular lesions in the sacubitril-treated animals compared to controls (glomerular injury score: 1.6±0.02 vs 0.9±0.08 au, p=0.034), and increased formation of protein casts (1.8±0.3 vs 1.3±0.2 au, p=0.034). Thus, in Dahl SS rats, administration of sacubitril at 125 μg/day had adverse effects on renal disease progression, especially glomerular damage and protein casts formation. In our prior study we showed that the combination of sacubitril at 75 μg/day with the angiotensin receptor blocker (ARB), valsartan, is effective to alleviate these outcomes. It is likely that the inhibition of neprilysin by sacubitril results in accumulation of Ang II and/or bradykinin and/or RAAS activation, which masks the beneficial effects of ANP level increase.