Renal nerves, renal inflammation and hypertension in deoxycorticosterone acetate (DOCA)‐salt hypertension: Who is in the driver's seat?

Hypertension (HTN) is the single‐greatest risk factor for cardiovascular disease and stroke – the two leading causes of morbidity and mortality worldwide. While the etiology remains debated, an increase in sympathetic nervous activity, particularly to the kidney (RSNA), and renal inflammation are regarded as primary contributors to the development and maintenance of HTN. Recently, targeted renal denervation (RDNx) has emerged as a novel therapy to treat resistant HTN and the associated renal pathology. However, the extent to which the benefits of this approach are due to ablation of afferent versus efferent renal nerves is unclear. Efferent RSNA is implicated in the trafficking of inflammatory T cells, and induction of chemo‐/cytokine production into the kidney. In addition, these inflammatory mediators are known to activate afferent sympathetic nerves. The present study was conducted to isolate the mechanistic relationships between efferent and afferent renal nerves, renal inflammation, and HTN in the deoxycorticosterone acetate (DOCA)‐salt rat model. We hypothesized that targeted ablation of afferent renal nerves (A‐RDNx) and total renal denervation (T‐RDNx) would attenuate the development of HTN. Further, we hypothesized T‐RDNx would obviate renal inflammation, while A‐RDNx will have no effect. Uninephrectomized male Sprague Dawley rats (275–300g) underwent A‐RDNx (n=10), T‐RDNx (n=10), or Sham (n=10) procedures. Following one week of baseline measurements, rats received 100mg DOCA (s.c.) and 0.9% saline to drink ad libitum. For 21 days, mean arterial pressure (MAP) and heart rate (HR) were monitored by radiotelemetry. Renal inflammatory T‐cells were measured by flow cytometry. Renal inflammation was further assessed by multiplex immunoassay of the following inflammatory chemo‐/cytokines: TNFα, IFNγ, IL‐1β, IL‐2, IL‐6, IL‐17a, GRO/KC, and MCP‐1. Cardiovascular data was averaged over 24 hours, and analyzed by one‐way ANOVA with a Bonferroni post‐hoc test (α=.05). Data presented as mean ± SEM. As hypothesized, DOCA‐salt increased (*p<.05) MAP, and T‐RDNx and A‐RDNx ameliorated (#p<.05) the HTN (see figure). No differences in HR, or sodium balance were observed between groups. Inflammatory CD4+ and CD8+ T‐cell infiltration was increased (*p<.05) with DOCA‐salt rats with intact renal nerves, and this was prevented (#p<.05) by T‐RDNx. Interestingly, whereas A‐RDNx attenuated HTN to the same degree as T‐RDNX, no effect on renal T‐cell infiltration was observed. Moreover, several renal inflammatory chemo‐/cytokines (GRO/KC, MCP‐1, IL‐2, IL‐6) were increased (*p<.05) with DOCA‐salt, and decreased (#p<.05) by T‐RDNx. Interestingly, A‐RNDx also attenuated (#p<.05) renal chemo/cytokine content. In summary, DOCA‐salt HTN was attenuated by T‐RDNx and A‐RDNx to the same extent. Further, renal inflammation signaling induced by DOCA‐salt was prevented by T‐RDNx and A‐RDNx, while only T‐RDNx prevented inflammatory T‐cell infiltration of the kidney. Together, these data suggest renal immune cell trafficking may be mediated by efferent RSNA in DOCA‐salt rats, but the HTN and renal inflammatory profile may be dependent on afferent RSNA. Indeed, these findings are clinically important in that targeted afferent RDNx, which leaves efferent sympathetic nerves intact, may be a novel therapy to treat HTN. Further study of the interaction between renal nerves and inflammatory signals is underway to elucidate this intriguing new role of afferent renal nerves. Support or Funding Information This study was supported in part by the NIHLBI 5RO1HL116476‐02 to J.W.O. C.T.B. is supported by NIHLBI 2T32HL7741‐21 Mean Arterial PressureHypertension induced by DOCA‐salt was ameliorated (#p<.05) similarly by total (T‐RDNx) and afferent‐specific (A‐RDNx) renal denervation (Control 107±6; *DOCA 132±12; #T‐RDNx 111±8; #A‐RDNx 117±5mmHg).