Three-Dimensional Imaging and Genetic Characterisation of a Rat Model of Polycystic Kidney Disease

Background: Polycystic kidney disease (PKD) is a congenital fibrocystic disorder for which there is no curative treatment. Consequently, PKD is classified as a medical condition with high unmet therapeutic need. Animal models with improved clinical translatability can optimally inform about potential efficacy of novel drug candidates for PKD. The polycystic kidney (PCK) rat is an established genetic model of PKD with natural history and renal histologic abnormalities that resemble the human disease. Gubra has established a PCK rat breeding program to enable fast turnaround time of preclinical drug discovery studies for PKD. In this study, we have characterised disease progression in the PCK rat to aid in designing future pharmacological intervention studies. Methods: Male PCK (PCK/CrljCrl-Pkhd1pck/Crl) and control (CRL:CD(SD)) rats were randomised into groups based on body weight at the age of 10 weeks. At the age of 17 and 25 weeks, rats underwent urine collection for quantification of albuminuria, and plasma sampling for analysis of urea and creatinine levels. At termination, kidneys were collected for RNAseq and imaging where 3D and total kidney volume, cyst number and volume were analysed using quantitative 3D light sheet imaging. Results: Compared to age-matched controls, PCK rats displayed marked albuminuria at 25 weeks of age. Plasma urea was progressively increased at both 17 and 25 weeks, while plasma creatinine was only increased at week 25. 3D light sheet imaging enabled whole-kidney counting of cysts and quantification of cyst volume (control: 11 mm3 vs 25 wks.: 414 mm3) as well as the total kidney volume. The PCK rats displayed differentiated expressed genes associated with angiogenesis, cellular stress, extracellular matrix remodelling, and inflammation. Conclusion: The PCK rat displays hallmarks of PKD, characterized by age-dependent progressive increase in biomarkers and regulation of genes associated with kidney injury, kidney hypertrophy and cyst formation. Quantitative whole-kidney 3D light sheet imaging is highly instrumental for detailed assessment of progressive kidney disease in the PCK rat. Accordingly, these imaging modalities are instrumental as key endpoints for assessment of potential therapeutic effects of preclinical drug candidates in the PCK rat model. Funding: Veterans Affairs Support - Veterans Affairs Support, Veterans Affairs Support