High-Salt Diet Modulates Afferent Nerve Expression Profiles; Interactions with the Endothelin System

Hypertension is often associated with an increased sympathetic nerve activity that contributes to sodium retention and exacerbation of blood pressure. Endothelin-1, which binds to endothelin A (ETA) and B (ETB) receptors, is strongly involved in the physiological control of systemic blood pressure during high salt dietary challenge; however, the role of these receptors on renal afferent nerves is less well known. We hypothesized that rats lacking ETB receptors on sensory nerves will have an altered response to a high-salt diet. Male and female rats lacking functional ETB receptors (ETB-def) on sensory nerves and transgenic littermate controls (TG) were fed a high salt (4.0% NaCl) or normal salt diet (0.49% NaCl) for 3 weeks. We collected dorsal root ganglia (DRG) from T8-L2 vertebral sections which contain the cell bodies of sensory nerves. The left-sided DRG had RNA isolated and bulk RNA sequencing performed, right-sided DRG were postfixed in PFA, cryo-embedded in OCT, and sections were stained for immunofluorescence to quantify the intensity of transient receptor potential vanilloid 1 (TRPV1) channel on neurons stained by neuronal nuclear protein (NeuN) channel. RNA sequencing data were analyzed by R studio and g.Profiler used for pathway analysis. Under high-salt diet, TRPV1 immunofluorescence signal was higher compared with rats on normal salt diet rats regardless of genotype or sex (104.7±5.4 vs. 80.0±3.6, n=3-5/group; p=0.0183). There were 9 differentially expressed genes (DEGs): Mgp, Gli1, Gfap, Igfbp6, Dync1h1, Cebpd, Slc13a4, Tf and C3 in TG male rats between normal and high-salt diets. ETB-def male rats under high-salt diets had 4 genes: Pi16, Fabp4, RGD1563270, and Osbpl8 which were differentially expressed compared to normal salt and that were unique from TG rats. TG female rats under high-salt diets had 13 significantly differentially DEGs: Sema3d, Megf9, Cers4, Strn, Itgav, Cpeb4, Dnm3, Itgb8, Ptprz1, Tyrp1, Mbnl, Selenot, Srgap1. There were no DEGs in ETB-def female rats under high-salt diets and normal salt diet. These data indicate that rats under high-salt diet have more a number of differentially expressed genes depending on the presence or absence of functional ETB receptors. These differential expressions could potentially lead to altered renal sensory nerve function and increased sympathetic activity. This research was supported by an NIH grant 1K01H159047 to BKB. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.