Isolating the Role of Renal Innervation in Renal Cystogenesis: Effect of Unilateral Renal Denervation in a Rat Model of Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder defined by a rapid onset of renal cyst formation and renal fibrosis early in development, ultimately leading to severe renal and cardiovascular dysfunction in early adulthood. There are limited treatment options to mitigate disease progression beyond renal transplantation. Our laboratory has reported a novel role for renal nerves in renal cyst progression, where bilateral renal denervation (RDNx) attenuated cystic progression from age week 4 (W4) through week 10 (W10) in the PCK rat model of ARPKD. Yet, the specific role of renal nerves in driving renal cysts remains unclear. The current study aimed to isolate the particular role for renal innervation in cystogenesis by performing a unilateral renal denervation (U-RDNx) and comparing the cystic and inflammatory progression in the contralateral sham-treated kidney from W4 – W10. We hypothesized that U-RDNx at W4 would slow cystic progression and lower markers of renal injury compared to the contralateral kidney at W10. To test this hypothesis, PCK rats (n=12; 6M/6F) underwent a unilateral renal denervation at W4, where the left or right kidney was randomly surgically denervated and the contralateral kidney underwent a sham procedure. Renal denervation was achieved by dissection of the periarterial nerves followed by 10% phenol application. Sterile saline was used for contralateral sham. At W10, renal tissues were assessed for morphometric effects followed by histological quantification of cystic index (% cystic area) and renal injury (glomerular fibrosis). Treatment and sex-dependent effects were analyzed by two-way ANOVA and Bonferroni post hoc test (*p<.05; two-tailed). Data presented as mean±SEM. At W10, no effect (p>.05) of U-RDNx was detected in bodyweight-normalized renal weights, volumes, and tissue density in male and female kidneys vs. contralateral Sham. No effect (p>.05) of denervation or sex was detected in cystic index (% cystic area); however, U-RDNx treated kidneys had lower (p<.05) glomerular fibrotic area in vs. contralateral sham (*17.1±5.0 vs. 24.3±5.6%). Interestingly, no sex differences were detected across these measurements. Overall, these findings partially support our hypothesis, where U-RDNx lowered glomerular fibrosis. However, we failed to detect an effect on renal cyst progression or renal morphometrics. Indeed, these data support the previous findings that renal innervation contributes to renal inflammation and injury in models of PKD. The differing cyst progression responses to bilateral vs. unilateral RDNx highlight a potential role for an extrarenal mechanism, specifically an ascending, afferent nerve mechanism mediating the differing effects. Further studies using unilateral afferent renal denervation are underway to further dissect the separate roles of renal sympathetic vs. afferent nerves in this model. Funding in part by NIH R01DK135573 (CTB); PKD Foundation Award 1022534 (CTB) This abstract was presented at the American Physiology Summit 2025 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.