Endothelin B Receptors are Necessary for Appropriate Renal Afferent Nerve Responsiveness

Abstract

Salt‐sensitive hypertension is a major health burden with end results of increased mortality and morbidity worldwide. Many factors contribute to salt‐sensitive hypertension including endothelin (ET) system dysfunction and aberrant sympathetic nerve activity. Previous work has highlighted the involvement of the ET system in modulating sympathetic tone; however, a complete understanding of the interactions involved remains elusive. Prior studies suggest that ETB receptors sensitize renal afferent nerves in response to high salt diet, which initiates a feedback loop via the renorenal reflex to inhibit efferent renal nerve activity and thus promote natriuresis. Rats lacking functional ETB receptors in all tissues except adrenergic tissues (ETB ‐def) are hypertensive, salt‐sensitive, and have elevated sympathetic tone. We have shown that bilateral renal denervation in ETB‐def rats attenuates blood pressure along with markers of global autonomic tone suggesting a role for afferent renal nerves in mediating hypertension in this model. Here, we hypothesized that ETB ‐def rats would have attenuated afferent nerve activation compared to transgenic (TG) controls. Renal pelvic walls were collected from TG and ETB ‐def rats and treated with prostaglandin E2 (PGE2). Substance P release was measured as an indicator of the activation of afferent nerves within the isolated pelvic walls. Substance P release was significantly higher in pelvic walls following treatment with PGE2 from TG compared to ETB ‐ def male rats (9.5 ± 2.8 vs. 0.1 ± 0.5 pg/min, p < 0.01, n = 5/group, respectively) and females (8.1 ± 1.2 vs. 0.7 ± 1.0 pg/min, p < 0.05, n = 5/group, respectively). Substance P release in response to capsaicin was not different between genotypes (4.2 ± 1.3 vs. 4.6 ± 1.8 pg/min, p = 0.85, n = 6/group, TG vs. ETB ‐def) indicating intact afferent nerve responsiveness. Preliminary data further indicate that ETB‐def animals do not display reduced renal sympathetic tone following a high salt diet. Rats were fed either a normal salt diet (0.49% NaCl) or high salt diet (4% NaCl) for 7–10 days, and total renal nerve activity was measured in anesthetized rats. TG controls tended to have lower nerve activity following high salt (1.8 ± 0.3 vs. 1.1 ± 0.2 mV.ms, n = 3–4/group, normal vs. high salt). Conversely, ETB‐def rats failed to display this reduction in sympathetic tone (1.8 ± 1.0 vs. 3.2 ± 0.3 mV.ms, n = 3/group, normal vs. high salt). These data indicate that salt‐sensitive ETB ‐def rats have impaired afferent renal nerve responsiveness, which results in a lack of renorenal reflex mediated sympathoinhibition.Support or Funding InformationSupported by T32 HL007457 to BKB, and P01 HL069999 and P01 HL136267 to DMP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.