Renal Afferent Nerve Activity and Association with Neurohumoral Dysregulation in a Model of Autosomal Recessive Polycystic Kidney Disease
Authors: Gauthier Madeline , Morales Mark , Banek Christopher 
Published: May 2024

Polycystic kidney disease (PKD) is a rare, genetic kidney disease characterized by cyst growth that leads to kidney failure. Renal nerves play an important role in the development and maintenance of hypertension and other renal diseases. Afferent (sensory) nerves convey information to the central nervous system in response to intrarenal stimuli. Our laboratory demonstrated that afferent renal nerve activity (ARNA) is elevated in 10-week-old PCK rats compared to non-cystic, age-matched Sprague-Dawley (SD) controls. Furthermore, ARNA positively correlated with cystic index (CI; a measure of cyst growth). To further elucidate the relationship between renal nerve activity, age, and cyst progression, we aimed to quantify both ARNA and renal sympathetic nerve activity (RSNA) in PCK and SD rats. We hypothesized that ARNA and RSNA would be greater in PCK than SD. Furthermore, arginine vasopressin (AVP) is elevated in PKD and increases cyst growth. There is evidence that activation of the afferent renal nerves can contribute to secretion of AVP. Thus, we propose that elevated ARNA increases AVP secretion, thereby increasing cyst growth. We also hypothesized that ARNA would positively correlate with age, CI, and copeptin (an indirect marker of AVP) in young PCK rats. To test our first hypothesis, we conducted direct renal nerve recordings in 10- to 12-week-old PCK (n=16;11M/5F) and 10-week-old SD (n=9;7M/2F) rats. For our second hypothesis, we conducted nerve recordings in 4- to 10-week-old PCK rats to evaluate the correlation of nerve activity with age, cystic index, and copeptin in animals ages 4- to 12-weeks-old (n=28;21M/7F). Multiunit nerve recording was performed under inactin anesthesia. As we previously published, a renal nerve bundle is isolated, placed on an iridium bipolar electrode, and encased in silicone. Resting RSNA was recorded following 10-minute stabilization period, then the nerve bundle was severed proximal to the electrode to isolate ARNA. ARNA recordings were normalized to maximal ARNA evoked by intrarenal 50 μM capsaicin. Comparisons between PCK and SD were analyzed by Student’s t-test (p<.05). Linear regression analyses were used to assess variable correlation (p<.05). Data presented as mean ± SEM. In contrast to our first hypothesis, RSNA did not differ between 10- to 12-week-old SD and PCK rats, whether measured via burst frequency (SD 6.92 ± 0.82; PCK *6.97 ± 0.34 Hz) or bursts/heart beat (SD 1.36±0.16; PCK 1.28 ± 0.06). ARNA was calculated as a percentage of maximal ARNA using either integrated ARNA (ARNAInt) or spikes/s (ARNASpikes). Baseline ARNAInt was greater in PCK rats (29.14±3.35%) than SD (13.46±2.08%, n=4), whereas PCK ARNASpikes trended (p=.06) higher than SD controls (SD 5.57±2.21; PCK 13.90±2.21%). In correlative analysis, RSNA trended (p=.05) to correlate with age in the PCK rat. However, there was no relationship between RSNA and (1) CI (p=0.29) or (2) copeptin (p=0.15). Similarly, there was no correlation detected between ARNA and age (ARNAInt: p=0.41; ARNASpikes: p=0.16) or serum copeptin (ARNAInt: p=0.96; ARNASpikes: p=0.20). ARNAInt trended (p=.07) to correlate with CI, but ARNASpikes did not correlate with CI (p=0.48). Overall, these data partially support our hypotheses. RSNA did not differ between SD and PCK rats, but ARNAInt was increased in PCK rats vs. SD. We failed to detect a correlation between either ARNA or RSNA and age, CI, or copeptin in PCK rats though, ARNAInt trended to correlate with CI. As ARNA does not appear to be correlated with serum copeptin, further studies are required to uncover the relationship between afferent renal nerves and cystogenesis in this model of PKD. PKD Foundation Research Award 1022534 (CB) NIDDK/PKD RRC Pilot and Feasibility Award U24DK126110 (CB) AHA 21PRE0000216068 (MG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.