Neprilysin Inhibition Attenuates Renin Cell Activation, Arteriolar Hypertrophy, and Kidney Injury Induced by Chronic Renin-Angiotensin System Suppression

Background: Long-term inhibition of the renin-angiotensin system (RAS) causes hyperactivation and phenotypic changes of renin cells, resulting in hypertrophy of the renal afferent arterioles. However, the impact of this arteriolar hypertrophy on renal function remains unclear. Atrial natriuretic peptide (ANP) suppresses renin secretion, yet its potential to counteract arteriolar hypertrophy has not been explored. Methods: A novel mouse model of afferent arteriolar hypertrophy was established by long-term administration of an angiotensin II receptor blocker (ARB) in wild-type C57BL/6NJ mice. To evaluate the functional impact, mice were assigned to three groups: control (vehicle), ARB (valsartan), and angiotensin receptor–neprilysin inhibitor (ARNI; sacubitril/valsartan). All treatments were administrated via oral gavage for 24 weeks. To investigate ANP’s effects on renin cells, we used As4.1 cells, a mouse-derived renin-expressing cell line. Cells were treated with ANP, a natriuretic peptide (NP) receptor antagonist, or a combination of both, followed by assessment of renin expression. Results: After 24 weeks, the ARB group exhibited elevated blood urea nitrogen and serum cystatin C levels compared to the controls, along with marked afferent arteriolar hypertrophy and cortical fibrosis on renal histology. In the ARNI group, plasma ANP levels were significantly higher than in the ARB group, despite comparable blood pressure levels. Although arteriolar hypertrophy was also observed in the ARNI group, the arteriolar diameter was significantly smaller than in the ARB group. Furthermore, the ARNI group showed reduced renin expression and secretion, improved renal function, lower injury marker levels, and attenuated cortical fibrosis compared to the ARB group. In As4.1 cells, ANP significantly suppressed renin expression, and this effect was abolished by co-treatment with the NP receptor antagonist. Conclusion: Chronic inhibition of RAS can cause renal dysfunction with afferent arteriolar hypertrophy. ANP suppresses renin cell activation through NP receptor signaling. Neprilysin inhibition, which increases circulating ANP levels, attenuates renin cell activation and arteriolar hypertrophy, thereby offering potential renoprotective effects.