Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review.

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD.

Sequential afferent and sympathetic renal denervation impact on cardiovascular and renal homeostasis in the male Sprague-Dawley rat.

Renal denervation (RDNx) is emerging as a promising treatment for cardiovascular disease, yet the underlying mechanisms and contributions of afferent (sensory) and efferent (sympathetic) renal nerves in healthy conditions remains limited. We hypothesize that sympathetic renal nerves contribute to long-term MAP and renal function, whereas afferent renal nerves do not contribute to the maintenance of cardiovascular and renal function. To test this hypothesis, we performed two experiments. In experiment one, we performed total renal denervation (T-RDNx), ablating afferent and sympathetic renal nerves, in normotensive adult SD rats to determine effects on MAP and renal function. Experiment 2 employed a sequential surgical ablation using: (1) afferent targeted renal denervation (A-RDNx), then (2) sympathetic (T-RDNx) denervation to determine the individual contributions to cardiovascular and renal homeostasis. In experiment 1, MAP decreased following T-RDNx and GFR increased. In experiment 2, A-RDNx led to an increase in MAP but did not change renal function. In contrast, T-RDNx decreased MAP and improved renal filtration. Together, these data partially support our hypothesis that renal sympathetic nerves contribute to the chronic regulation of arterial pressure and renal function. Contrary to the hypothesis, A-RDNx produced an increase in MAP without a detected change in renal function. We concluded that renal sympathetic nerves influence MAP and renal function regulation through a well-defined tonic contribution to renal vascular resistance and sodium reabsorption, whereas afferent renal nerves likely contribute to the maintenance of MAP through a tonic sympatho-inhibitory, negative feedback regulation in the normotensive, healthy rat.

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

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.