Increased Renal Sensory Neuron Excitability Independent of Renal Cystic Severity in the PCK Rat Model of Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a rare, genetic kidney disease characterized by renal cyst formation and progression that eventually leads to kidney failure. Our lab has recently reported a novel role for renal sensory nerves and increased sensory nerve activity in the progression of renal cystogenesis in the PCK rat model of PKD. However, it remains unclear whether the progression of renal cystogenesis directly contributes to increased ARNA. We aimed to address the changes in renal sensory nerve activity and function with respect to age and renal cystic severity in the PCK rat model. We hypothesized that aged PCK rats would exhibit greater cystic progression compared to young cohorts, and both age and renal cystic index would correlate with higher renal sensory nerve excitability.To test this hypothesis, dorsal root ganglia (DRG; T10–L1) were isolated from female PCK rats young (4-36 weeks, n=21 animals) and aged (41-45 weeks, n=8 animals) for whole-cell patch clamp recordings to measure action potential frequency (AP Hz). A bilateral subcapsular intrarenal injection of DiI (10uL; 10mg/ml) was used to retrogradely label renal-specific DRG neurons (rDRGNs). DRGs were collected six days after labeling, enzymatically and mechanically dissociated to collect rDRGNs. The neurons were seeded on poly-lysine coated glass coverslips and cultured overnight. Whole-cell patch-clamp recordings were performed < 24 hours after isolation. Kidneys were also collected for histological analysis of cystic index, calculated as % cystic area. Sections were stained with hematoxylin and eosin, and cystic index was quantified using ImageJ by normalizing the cystic area to the total kidney area. Data are presented as mean+/-SEM. Data were analyzed by linear regression and 2-way ANOVA with Bonferroni posthoc test, and p< .05 was considered significant. Comparing rDRGN excitability across young and aged cohorts, the aged PCK rats displayed markedly higher (p< .05) AP frequency compared to the young female PCK cohort. Specifically, peak AP frequency in aged rDRGNs was elevated (p< .05) at highest current step (300pA) (19.4±4.1 vs. 7.5±1.6 Hz). Linear regression analysis also revealed a positive association (p<. between age in weeks and rDRGN AP frequency, showing a progressive increase with time. In contrast, we failed to detect a difference in renal cystic index between young and aged PCK females (9.9±1.0 vs. 10.5±1.9 % cystic area), and there was no correlation of rDRGN AP frequency with cystic index. Collectively, these data partially support our hypothesis, where aged PCK rats have elevated rDRGNs excitability compared to the young cohort. These findings indicate that rDRGNs excitability increases with age in PCK rats and may underlie the elevated ARNA observed in advanced PKD. Importantly, this elevated rDRGN excitability independent of increased cystic index suggests changes in renal-afferent pathways may occur independently from cyst progression. Together, these findings show that aging-related changes in sensory neurons in PKD and warrant further investigation into the mechanisms driving increased excitability in rDRGs. We speculate the loss of function mutation in fibrocystin which underlies the PCK rat pathophysiology may have direct effects on rDRGN function. Studies are underway to test the role of fibrocystin in sensory neuron function. 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.