SPARC: Renal Denervation Attenuates DOCA‐salt Hypertension in the Mouse

Abstract

Hypertension affects approximately one third of the adult population in the United States. Catheter based renal denervation (RDN) has emerged as a novel treatment for hypertension in patients. However, the mechanisms by which RDN lowers arterial pressure has not been fully determined. We hypothesize that an interaction between renal nerves (afferent and efferent) and renal inflammation contributes to hypertension. To test this hypothesis, we utilized a model of hypertension in the mouse produced by the combination of uni‐nephrectomy with deoxycorticosterone acetate (DOCA) and a high salt diet (DOCA‐salt). 10‐week‐old male C57BL6/J mice were implanted with radio‐telemetry probes in the carotid artery for measurement of arterial pressure. DOCA was administered via subcutaneous implantation of a silicon pellet containing 50 mg of DOCA. Sham mice received a drug free silicon pellet. Uni‐nephrectomy, pellet insertion, salt treatment, and RDN were all performed or started on the same day. RDN was performed through surgical ablation and peri‐axonal application of 10% phenol. Baseline arterial pressure was measured 3 days prior to induction of DOCA‐salt hypertension by radiotelemetry. Separate cohorts of mice were generated for protein quantification and histology, with urine and kidneys harvested 21 days post induction of DOCA‐salt hypertension. Cytokine protein quantification was obtained through Multiplex ELISA. All errors reported are SEM. Following 7 days of DOCA‐salt, mean arterial pressure (MAP) increased +44.8 ± 3.2 mmHg from baseline (153.1± 1.8 mmHg day 7 absolute value), comparted to −1.5 ± 5.5 mmHg in sham mice (105.6 ± 0.5 mmHg day 7 absolute value). RDN reduced this increase by more than 50% in RDN‐DOCA‐salt mice (+20.5 ± 5.0 mmHg delta, 131.6 ± 8.1 mmHg absolute). Renal and urinary cytokines and chemokines were increased in DOCA‐salt compared to sham treated mice. For example, renal MCP‐5 was 24.7 ± 7.2 pg/mg in DOCA‐salt mice compared to 5.0 ± 0.6 pg/mg in sham treated mice. Similarly, urinary MCP‐5 was significantly higher in in DOCA‐salt mice (12.4 ± 5.1 pg/mg) compared to sham mice (2.1 ± 1.1 pg/mg). IL‐1α and IL‐1β were both increased in DOCA‐salt kidneys (112.4 ± 19.2 pg/mg and 2.1 ± 0.4 pg/mg respectively) compared to sham kidneys (31.98 ± 4.4 pg/mg and 0.36 ± 0.06 pg/mg respectively). We also measured, by immunohistochemistry, an increase expression of the IL‐1 receptor in kidneys of DOCA‐salt mice compared to sham controls. We hypothesize that renal cytokines activate renal afferent nerves and ultimately elevate arterial pressure by activation of the sympathetic nervous system. Future studies will test this hypothesis by examining whether elimination of cytokine generated afferent nerve activity attenuates hypertension in DOCA‐salt mice.Support or Funding InformationNIH: R01HL116476, MnOPT: T32DK083250–01A1, SPARC: 5U01DK116320‐03