Contributions of afferent and sympathetic renal nerves to cystogenesis and arterial pressure regulation in a preclinical model of autosomal recessive polycystic kidney disease.

Abstract

Polycystic kidney disease (PKD) is the most common inheritable cause of kidney failure, and the underlying mechanisms remain incompletely uncovered. Renal nerves contribute to hypertension and chronic kidney disease-frequent complications of PKD. There is limited evidence that renal nerves may contribute to cardiorenal dysfunction in PKD and no investigations of the role of sympathetic versus afferent nerves in PKD. Afferent renal nerve activity (ARNA) is elevated in models of renal disease and fibrosis. However, it remains unknown if this is true in PKD. We tested the hypothesis that ARNA is elevated in a preclinical model of autosomal recessive PKD and that targeted renal nerve ablation would attenuate cystogenesis and cardiorenal dysfunction. We tested this by performing total renal denervation (T-RDNx) or afferent renal denervation (A-RDNx) denervation in 4-wk-old male and female PCK rats and then quantified renal and cardiovascular responses 6 wk following treatment. Cystogenesis was attenuated with A-RDNx and T-RDNx versus sham controls, highlighting a crucial role for renal afferent nerves in cystogenesis. In contrast, blood pressure was improved with T-RDNx but not A-RDNx. Importantly, treatments produced similar results in both males and females. Direct renal afferent nerve recordings revealed that ARNA was twofold greater in PCK rats versus noncystic controls and was directly correlated with cystic severity. To our knowledge, we are the first to demonstrate that PCK rats have greater ARNA than noncystic, age-matched controls. The findings of this study support a novel and crucial role for renal afferent innervation in cystogenesis in the PCK rat.NEW & NOTEWORTHY This is the first study to dissect the contributions of renal sympathetic and afferent innervation in the PCK rat, a preclinical model of autosomal recessive polycystic kidney disease. We demonstrated that resting afferent renal nerve activity is greater in the PCK rat than noncystic controls and that basal afferent renal nerve activity is directly correlated with the extent of renal cystogenesis.