Afferent renal nerves mediate hypertension and renal cystogenesis in a preclinical model of polycystic kidney disease
Authors: Banek Christopher T. , Gauthier Madeline M. , Osborn John W. 
Published: June 2021

Polycystic kidney disease (PKD) remains a debilitating and chronic condition, and a common cause of end‐stage renal disease. In addition to renal pathology, hypertension is often presented. Renal sympathetic nerves are well‐known to contribute to renal function and arterial pressure homeostasis, which in turn, may be a novel therapeutic target for hypertension in PKD. Moreover, ablation of the renal sympathetic nerves purportedly mitigates cystic development in a preclinical model of PKD; however, the contribution of efferent of afferent renal nerves in this effect remains unknown. We recently developed a novel method to specifically ablate afferent renal nerves, leaving efferent nerves intact. In this study, we aimed to elucidate the role of renal sympathetic nerves in PKD‐induced hypertension and cystic development, as well as reveal the contribution of the individual efferent and afferent renal nerve populations. We hypothesized efferent renal nerves mediate renal cystogenesis and hypertension in the PKD rat, whereas afferent renal nerves play no role in this disease. To test this hypothesis, we performed a bilateral renal denervation (RDx), afferent‐specific RDx (ADx), or sham surgery on four‐week‐old male and female PKD rats (total n=36; 12/group; 6M/6F). Arterial pressure was measured by radiotelemetry. At 10 weeks of age, rodents were euthanized, and renal samples were collected for blinded histological analysis of cystic development. Renal function was estimated by plasma creatinine (PC) and blood urea nitrogen (BUN). Data was analyzed by a two‐way ANOVA, across sex and treatment groups (α=0.05). Data presented as mean+SEM. At 10 weeks of age, 24‐hour mean systolic arterial pressure (SBP) was lower (p<.05) in RDx (125±2) and ADx (123±3) vs. Sham (132±3 mmHg). Renal cystic index (%cyst/total area) was also reduced (p<.05) in both RDx (9.6±2.1%) and ADx (10.1±1.6%) compared to Sham (14.7±1.9%). No influence of sex was observed in either SBP or cystic index. No effect of treatment or sex was observed on indirect measurements of renal function (i.e. PC and BUN). Based on these findings, we reject our original hypothesis, as ADx mirrored the arterial pressure and cystogenesis effects observed with ablation of both efferent and afferent nerves (i.e. RDx). We conclude that afferent renal nerves contribute to the renal cystogenesis and hypertension in this model of PKD, in which either targeted ablation of afferent renal nerves may be a novel and effective therapeutic approach to PKD treatment. Though the mechanism of ADx treatment remains unclear, we hypothesize that afferent renal nerves mediate cystogenesis and arterial pressure through the suppression vasopressin (AVP), as AVP release is mediated in part by afferent renal nerve activation. Additionally, pharmacological antagonism of AVP activity (i.e. V2 receptor inhibition) in the collecting ducts is an effective clinical therapy to suppress PKD cystogenesis. Further studies are currently underway to elucidate the role of AVP regulation as a potential mechanism by which afferent nerves mediate renal cystogenesis and hypertension in this model.Support or Funding InformationThis project was supported in part by NIH HL116476 (JWO) and AHA 17POST33661003 (CTB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.