Hypertension Precedes Changes in Afferent Renal Nerve Activity and Renal Dysfunction in DOCA‐Salt Rat Model
Authors: Parvin Irin , Gauthier Madeline , Dennis Melissa R. , Morales Mark , Banek Christopher T. 
Published: May 2022

Hypertension (HTN) is a major risk factor for cardiovascular disease, which is a leading cause of morbidity and mortality worldwide. Though the etiology of HTN is multifaceted, one important contributor is aberrant autonomic signaling, both to (sympathetic nerve activity; SNA) and from (afferent renal nerve activity; ARNA) the kidney. ARNA is reportedly elevated in several models of HTN, and ablation of the renal afferent nerves can lower arterial pressure. It remains unknown, however, when this increase occurs in comparison to the cardiovascular and renal function in the hypertensive paradigm. The aim of the study was to determine whether ARNA mirrors the increase in arterial pressure and decline in kidney function in a preclinical model of salt‐sensitive HTN. We hypothesized that increased ARNA would increase in parallel to arterial pressure (AP) and the decline in renal function in the DOCA‐salt rat model.

To test the hypothesis, 20 adult male Sprague Dawley rats (275‐325 g) underwent a unilateral nephrectomy followed by two‐weeks for recovery. Next, deoxycorticosterone acetate (DOCA; 100mg, s.c.) was implanted, and henceforth animals were maintained on 0.9% saline drinking water ad libitum. Cardiovascular and renal measurements were collected weekly. Mean systolic blood pressure (SBP) were measured weekly by tail‐cuff, and renal function was estimated weekly by serum creatinine (Cr). Animals were randomly assigned to undergo multiunit ARNA recording on protocol day (D) 0, D7, D14, or D21. ARNA recordings were performed under urethane anesthesia (1500mg/kg, IP) as previously described. ARNA was isolated by sectioning the proximal end of the nerve bundle, and recorded for 10 minutes following preparation. Activity was rectified and integrated over 50ms and normalized to maximal ARNA achieved by intrapelvic 50µM capsaicin. Data were analyzed by one‐way repeated‐measures ANOVA with Bonferroni post‐hoc test (α=0.05). Data presented as mean±SEM.

ARNA (presented as %ARNAmax) is increased (p<0.05) at D21 and D14 vs. baseline, but no detectable changes were observed at D7. Mean SBP progressively increased at D7, D14, and D21 vs. all prior weeks. Serum creatinine increased (p<.05) at D14 and D21 vs. baseline, indicating a time‐dependent decline in kidney function. Necropsy data demonstrate kidney weight was increased (p<.05) only on D21 compared to baseline, and no differences were detected at D7 and D14 vs. D0. In contrast, heart weights were greater (p<.05) on D14 and D21 vs. baseline.

Collectively, these data partially support our hypothesis that ARNA increases in parallel with increasing AP in the DOCA‐salt model; however, AP appears to increased independent of detectable changes in both ARNA and renal dysfunction. Interestingly, renal dysfunction and ARNA were detected at similar times (D14), potentially highlighting to a closer physiological relationship between ARNA and renal function. The onset of HTN prior to changes in ARNA and renal dysfunction delineate these variables from the early stages of this HTN model; however, we can not rule on the contributions of ARNA and renal dysfunction as the model progresses. Further studies on the timing of ARNA activators such as renal inflammation or fibrosis are underway to further elucidate the connection of renal function decline and ARNA.