Cyst Fluid From a Rat Model of ARPKD Has a Unique Electrolyte Composition and Sexually Dimorphic Metabolite Profile

Polycystic kidney disease (PKD) is characterized by large fluid-filled cysts that lead to end-stage renal disease. Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder characterized by the formation of fluid-filled cysts in the kidneys. The aim of this study was to determine the electrolyte and metabolite composition of cyst fluid from a rat model of polycystic kidney disease. We used the PCK rats, a model of ARPKD (male and female rats, 12-14 wks) and performed the analysis of electrolytes in cystic fluid, urine, and plasma. Cystic fluid from the PCK rats had a unique and consistent electrolyte profile. The cyst fluid contained higher K + (95.2 ± 3.1 mM) than plasma values. The Na + (23.7 ± 1.2 mM) and Cl - (65.5 ± 2.1 mM) concentrations were both significantly lower than the plasma and urinary levels. The cystic Ca 2+ (0.41 ± 0.05 mM) concentration was significantly less than plasma but not urine. Beyond this, cyst fluid had significantly greater glucose levels (69.6 ± 2.1 mg/dL) and lower creatinine concentrations (1.61 ± 0.19 mM) compared to urine. No significant differences between male and female cyst electrolyte concentrations were observed. Using the GHK equation with textbook intracellular concentrations and permeabilities and replacing the extracellular concentrations with the measured cyst values predicts the resting membrane potential of cyst epithelia is highly depolarized (around 0 mV). Calcium imaging from ex vivo ARPKD rat cyst epithelia determined that their basal intracellular Ca 2+ concentration in a high Na + , low K + , 2 mM Ca 2+ imaging solution is 96 ± 9 nM. Ongoing studies will determine how a low Na +, high K + , 0.4 mM Ca 2+ imaging solution that more accurately represents the apical cyst electrolyte environment impacts basal intracellular Ca 2+ levels and membrane depolarization. We further performed untargeted metabolomic profiling and identified 5,593 distinct mas peaks. Male and female cyst fluid had unique chemical signatures; over 2,000 compounds are differentially expressed between sexes. Tryptophan metabolism was identified as the primary metabolic pathway with the largest number of compounds that were significantly different between males and females. Additionally, amino acids and peptides were the predominant chemical class identified in cyst fluid. In summary, cyst fluid from a rat model of ARPKD has a unique and sexually dimorphic chemical signature. Understanding its composition will provide greater insight into ion transport and metabolic behavior of cyst epithelia, potentially leading to novel therapeutic strategies. K99 HL153686, R35 HL135749, BX004024, R01 DK126720, DK129227 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.