Renal denervation arrests progression of proteomic changes while reversing hypertension in DOCA-salt rats

Three quarters of those diagnosed with hypertension remain uncontrolled. Renal denervation (RDN) is a promising FDA-approved treatment for hypertension. However, the use of RDN is limited because patient response to this procedure is variable and unpredictable. Further analysis into the signaling pathways underlying RDN’s efficacy are critical to guide patient selection. We aim to analyze the renal proteome to assess pathways activated/inactivated in hypertensive rats which were impacted by RDN, hypothesizing that RDN would reverse the effects of DOCA treatment on renal protein abundance.To address this hypothesis, deoxycorticosterone acetate (DOCA; 100mg, s.c.) or vehicle (VEH; silicone pellet, s.c.) was implanted in uninephrectomized male rats (n=4) to induce hypertension. Rats were offered 0.9% saline ad libitum throughout. At 21 days, kidney tissue was harvested, snap frozen, and processed for quantitative proteomic analysis from vehicle rats (VEH) and from DOCA-salt rats (D-21). Two additional DOCA groups were also generated to address the reversal effects of RDN, where one group underwent RDN on day 21 and the other underwent sham surgery. These rats then continued to receive saline ad lib and were followed another 21 days, until tissue collection on day 42 (D-42RDN n=4/group). Blood pressures were measured at primary endpoints by tail-cuff plethysmography. Tail-cuff systolic BP was increased after 21 days DOCA treatment relative to VEH (192.3±18.4 vs. 142.8±11.2, p< 0.05). RDN decreased BP by 42 days compared to sham control (D-42RDN: 166.8±11.7 vs. D-42Sham: 203.6±8.3, p< 0.05). Proteomic analysis quantified 3899 proteins from isolated kidney tissue. Principal component analysis revealed significant global proteomic changes between VEH and D-21. Interestingly, D-42RDN rats were globally similar to D-21, while D-42Sham rats are significantly different from either. Consistent with this finding from PCA, we find that between D-21 and D-42Sham there are 607 proteins with differential expression (p < 0.05) whereas between D-21 and D-42RDN there are only 48. Between D-21 and D-42Sham, significant differences were detected in pathways including regulation of complement (24 proteins, p=7.8x10-12), ferroptosis (14 proteins, p=2.2x10-7) and regulation of TRP channels (14 proteins, p=5.8x10-3). In contrast, between D-21 and D-42RDN, significant differences were found in pathways including response to xenobiotic stimulus (5 proteins, p=2.5x10-3) and lauric acid metabolism (2 proteins, p = 4.2x10-3).Our proteomic analysis, combined with blood pressure data, suggests that RDN arrests the progression of the pathologic changes associated with extended DOCA-salt hypertension. Interestingly, while the changes on the protein level are simply arrested, blood pressure is significantly decreased by RDN. These studies also confirm the inflammatory state induced by DOCA-salt hypertension is alleviated by RDN, with significant changes in complement regulation and ferroptosis. Further studies into these mechanisms will help guide patient selection and optimize use of RDN to treat hypertension. This abstract was presented at the American Physiology Summit 2026 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.