Abstract
Abstract Background and Aims Polycystic kidney disease (PKD) is a congenital fibrocystic disorder where cysts are primarily forming within the kidneys causing enlargement, loss of kidney function and resulting in chronic kidney disease 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 clinical 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. Method Male PCK (PCK/CrljCrl-Pkhd1pck/Crl) and control (CRL:CD(SD)) rats (Charles River) were randomised into groups based on body weight at the age of 10 weeks. At the age of 17 and 25 weeks, rats underwent ultrasound assessment of kidney volume, urine collection for quantification of albuminuria, and plasma sampling for analysis of urea and creatinine levels. At termination, whole kidneys were harvested and total kidney volume, cyst number and cyst volume were analysed using quantitative 3D light sheet imaging. Results Compared to age-matched control rats, PCK rats displayed marked albuminuria which was significantly increased at week 25 of age. Whereas plasma urea was progressively increased at both time points, plasma creatinine increased at week 25. Ultrasound measurements revealed that total kidney volume progressive increased compared to control rats. 3D Light sheet imaging enabled whole-kidney counting of cysts and quantification of cyst volume as wells as the total kidney volume that closely correlated to kidney ultrasound results. Conclusion The PCK rats displays histological hallmarks of PKD, characterized by age-dependent progressive increases in biomarkers of kidney injury, kidney hypertrophy and cyst formation. In vivo ultrasound and ex vivo quantitative whole-kidney 3D light sheet imaging is highly instrumental for detailed assessment of progressive disease in the PCK rat. The renal histopathological markers may serve as key histological endpoints for assessment of therapeutic effects of preclinical drug candidates in this translational rat model of PKD.
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