NATRIURETIC PEPTIDES SUPPRESS RENIN CELL HYPERACTIVATION INDUCED BY LONG-TERM RENIN-ANGIOTENSIN SYSTEM INHIBITION AND ATTENUATE HYPERTROPHY OF RENAL AFFERENT ARTERIOLES.

Long-term inhibition of the renin-angiotensin system (RAS) leads hyperactivation and phenotypic changes of renin cells, resulting in hypertrophy of the renal afferent arterioles. However, the mechanisms to counteract these changes remain unclear. Natriuretic peptides (NPs) are known to act antagonistically against the RAS, promoting natriuresis, lowering blood pressure, and suppressing renin release. We therefore hypothesized that NPs suppress renin cell activation and attenuates afferent arteriolar hypertrophy.

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 impact of NPs on ARB-induced changes, mice were assigned to three groups: control (vehicle), ARB (valsartan), and angiotensin receptor–neprilysin inhibitor (ARNI; sacubitril/valsartan). All treatments were administered once daily by oral gavage for 24 weeks. All mice were administered body weight-adjusted NaCl and maintained on a sodium-restricted diet, with free access to drinking water. Quantitative RT-PCR in kidney tissue, ELISA, and histological analysis were performed. Single-nucleus RNA sequencing (snRNA-seq) was conducted using kidney cortices. To investigate direct effects of NPs on renin cells, we used As4.1 cells, a mouse-derived renin-expressing cell line. Cells were treated with atrial natriuretic peptide (ANP), an NP receptor antagonist, or both, followed by assessment of renin gene expression. To explore the relationship between long-term RAS inhibition and NPs in the human kidney, the thickness of afferent arteriolar walls was analyzed using renal biopsy samples from patients on long-term RAS inhibition with atrial fibrillation, a condition known to increase NP levels due to atrial distension.

In mice, the ARB group exhibited elevated blood urea nitrogen and serum cystatin C levels compared with controls, along with marked afferent arteriolar hypertrophy and cortical fibrosis on renal histology. In the ARNI group, plasma ANP levels were significantly higher than those in the ARB group, despite comparable blood pressure levels. Although arteriolar hypertrophy was also observed in the ARNI group, the mean arteriolar wall thickness was significantly smaller than in the ARB group. Furthermore, the ARNI group showed reduced renin expression and secretion, preserved renal function, and lower renal injury marker levels compared with the ARB group. In the snRNA-seq analysis, various renal cell clusters were identified and compared among treatment groups, revealing several differentially expressed genes and pathways between the ARB and ARNI groups. In As4.1 cells, ANP significantly suppressed renin gene expression, and this effect was abolished by co-treatment with the NP receptor antagonist. Renal biopsy samples from patients with atrial fibrillation showed significantly smaller afferent arteriolar wall thickness compared with those from patients without atrial fibrillation who had received comparable long-term RAS inhibition. 

NPs attenuate chronic RAS inhibition–induced renin cell hyperactivation and afferent arteriolar hypertrophy, thereby exerting a renoprotective effect.