Vascular Function Impairment Precedes Decline in Renal Function in a Model of Autosomal Recessive Polycystic Kidney Disease

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder that is characterized by the rapid growth of renal cysts. Though the renal disease progression in ARPKD has been well-defined, the temporal relationship with vascular function in ARPKD progression remains unclear. In this study, we aimed to quantify vascular function and time-dependent relationship with renal dysfunction in a preclinical model of ARPKD. We hypothesized that peripheral vascular dysfunction would precede any decline in renal function in the PCK rat model of ARPKD.Experiments were conducted in young PCK animals (10 weeks; n=5; 2M/3F), mature PCK animals (30 weeks; n=16; 8M/8F) and age matched, non-cystic Sprague-Dawley controls (Young; n=5; 5M) (Mature; n=4; 4M). Renal function was estimated by serum creatinine (Cre) and blood urea nitrogen (BUN). Vascular function was assessed ex vivo by Mulvany wire myography on second-order mesenteric arteries. Endothelial and smooth muscle vasodilatory function were assessed by dose responses (10-11-10-5M) to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively, following preconstriction to thromboxane mimetic U46619 (10-4M). Final relaxation is reported as a percentage of maximum relaxation (%max). Data were compared across strains and age by two-way ANOVA with Bonferroni post hoc test (*p<.05). Data are presented as Mean±SEM.Ach-mediated relaxation in the young PCK rats was lower vs. age-matched SD controls (*43.9±9.6 vs. 86.1±1.9 %max), and no effect was detected on EC50Ach. In contrast, there was no difference in final Ach-mediated relaxation in mature PCK rats compared to age-matched controls. EC50Ach was also lower in mature PCK rats vs. age-matched SD controls (*1.8±0.4x10-8 vs. 3.1±1.1 x10-7M). Comparing across ages, final relaxation to Ach was higher (*p<.05) in mature PCK rats compared to young PCK. EC50Ach was also lower (*p<.05) in mature vs. young PCK cohorts (8.8±2.7 x10-8 M). SNP responses did not vary with respect to either age or strain. No sex dependent differences were detected. Importantly, no differences were detected in serum BUN and Cr between SD and PCK cohorts at both age groups.Together, these data partially support our initial hypothesis that vascular dysfunction in ARPKD precedes changes in renal function. As predicted, endothelial-dependent vasodilatory function was impaired in the 10-week-old PCK rats compared to SD controls. Surprisingly, endothelial function improved over time in the mature (30-week-old) PCK rats, observed as increased Ach-mediated relaxation, even higher than age-matched SD controls. This shift in PCK rat endothelial function and Ach-sensitivity appears to be independent of a decline in renal function. The cellular mechanisms underlying this shift remain unknown, and further studies are underway to quantify the intracellular signaling and receptor expression changes potentially underlying this shift over time in the PCK rat model of ARPKD. R00HL141650 (CTB), U24DK126110-20765 (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.