Role of Renal Nerves in a Preclinical Model of Advanced Autosomal Recessive Polycystic Kidney Disease
Authors: Gauthier Madeline , Encinas Noah , Dennis Melissa , Morales Mark , Banek Christopher 
Published: May 2023

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disease defined by the early and rapid renal cyst growth, which result in renal and cardiovascular dysfunction in early adulthood. Our lab has recently revealed a novel role for renal nerves in early phase of renal cystogenesis in the PCK rat model of ARPKD, where total renal denervation (T-RDNx) mitigated cystic progression from age week 4 (W4) through W10. Moreover, afferent-targeted renal nerve ablation (A-RDNx), which leaves sympathetic nerves intact, also suppressed renal cystogenesis, highlighting a pivotal role of renal afferent nerves in the PCK rat cystic progression. Whether renal nerves contribute to later phases of ARPKD progression remains unknown. In this study, we aimed to evaluate the role of renal nerves in cystogenesis and cardio-renal dysfunction in 24-week-old PCK rats. We hypothesized that T-RDNx but not A-RDNx, would improve renal function and decrease systolic blood pressure (SBP), but that intervention would not decrease cystogenesis. To test this hypothesis, PCK rats (age: Week 24; W4) were randomly treated with T-RDNx (n=12; 7M/5F), A-RDNx (n=15; 7M/8F), or sham (n=13; 6M/7F) surgical interventions. Animals were monitored biweekly for cardiovascular and renal function measurements through W30. SBP was collected via tail cuff. Renal function was assessed indirectly by serum creatinine (Cr) and blood urea nitrogen (BUN). At W30, kidney tissues were collected and assessed for cystic index (%cystic area). Treatment and sex effects were analyzed by two-way ANOVA with a Bonferroni post hoc test (p<.05; two-tailed). Data presented as mean±SEM. Prior to treatment, no difference in cardiovascular and renal function was detected between sexes or treatment groups. Following treatment, SBP responses were lower in T-RDNx rats at weeks 1 (-20.1±3.4 mmHg), 2 (-15.4±3.5 mmHg), and 3 (-13.6±2.6 mmHg) compared to Sham (W25: -2.27±5.3 mmHg; W26: -0.9±4.1 mmHg, W27: 0.1±2.7 mmHg). No effect of sex was detected in SBP responses. Regarding renal function effects - we failed to detect any difference in serum Cr and BUN between groups or sexes at any point in the study. Finally, cystic index was assessed at W30, where both T-RDNx (6.8±1.1%) and A-RDNx (7.6±1.3%) were less than Sham (11.9±1.5%). No effect of sex was detected. These findings partially support our hypothesis that SBP would decrease only with T-RDNx. In contrast to our hypothesis, cystogenesis was reduced in both T-RDNx and A-RDNx groups, independent of detected changes in renal function or injury. These studies complement our previous findings in weanling (W4) PCK rats, where afferent renal nerves continue to contribute to renal cystogenesis, whereas the renal sympathetic nerves play a critical role in blood pressure regulation. Though these studies support the role for renal denervation to mitigate early and late-phase ARPKD, further studies are required to dissect this important and novel mechanism. R00HL141650 (CTB), U24DK126110-20765 (CTB), Doris Duke Charitable Foundation (CTB), AHA 21PRE216068 (MMG) This is the full abstract presented at the American Physiology Summit 2023 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.