TY - JOUR
T1 - The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease
AU - Arroyo, Jennifer
AU - Escobar-Zarate, Diana
AU - Wells, Harrison H.
AU - Constans, Megan M.
AU - Thao, Ka
AU - Smith, Jessica M.
AU - Sieben, Cynthia J.
AU - Martell, Madeline R.
AU - Kline, Timothy L.
AU - Irazabal, Maria V.
AU - Torres, Vicente E.
AU - Hopp, Katharina
AU - Harris, Peter C.
N1 - Funding Information:
We thank the pathologists Roger K. Moreira and Mariam P. (Priya) Alexander for analysis of the histological data; Slobodan I. Macura, Prasanna K. Mishra, Ryan Meloche, and the NMR Core Facility for assistance in animal imaging; and Lisa Vaughan for statistical discussions. This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK058816 (PCH) and Polycystic Kidney Disease Center grant P30 DK090728 (VET). The study was also supported by the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational Polycystic Kidney Disease Center, Navitor Pharmaceuticals (PCH) and the Zell Family Foundation. JA and CJS were supported by the Mayo Nephrology T32 Training grant DK007013, and JA was also supported by F31 grant DK105778.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/6
Y1 - 2021/6
N2 - Autosomal dominant polycystic kidney disease (ADPKD), primarily due to PKD1 or PKD2 mutations, causes progressive kidney cyst development and kidney failure. There is significant intrafamilial variability likely due to the genetic background and environmental/lifestyle factors; variability that can be modeled in PKD mice. Here, we characterized mice homozygous for the PKD1 hypomorphic allele, p.Arg3277Cys (Pkd1RC/RC), inbred into the BALB/cJ (BC) or the 129S6/SvEvTac (129) strains, plus F1 progeny bred with the previously characterized C57BL/6J (B6) model; F1(BC/B6) or F1(129/B6). By one-month cystic disease in both the BC and 129 Pkd1RC/RC mice was more severe than in B6 and continued with more rapid progression to six to nine months. Thereafter, the expansive disease stage plateaued/declined, coinciding with increased fibrosis and a clear decline in kidney function. Greater severity correlated with more inter-animal and inter-kidney disease variability, especially in the 129-line. Both F1 combinations had intermediate disease severity, more similar to B6 but progressive from one-month of age. Mild biliary dysgenesis, and an early switch from proximal tubule to collecting duct cysts, was seen in all backgrounds. Preclinical testing with a positive control, tolvaptan, employed the F1(129/B6)-Pkd1RC/RC line, which has moderately progressive disease and limited isogenic variability. Magnetic resonance imaging was utilized to randomize animals and provide total kidney volume endpoints; complementing more traditional data. Thus, we show how genetic background can tailor the Pkd1RC/RC model to address different aspects of pathogenesis and disease modification, and describe a possible standardized protocol for preclinical testing.
AB - Autosomal dominant polycystic kidney disease (ADPKD), primarily due to PKD1 or PKD2 mutations, causes progressive kidney cyst development and kidney failure. There is significant intrafamilial variability likely due to the genetic background and environmental/lifestyle factors; variability that can be modeled in PKD mice. Here, we characterized mice homozygous for the PKD1 hypomorphic allele, p.Arg3277Cys (Pkd1RC/RC), inbred into the BALB/cJ (BC) or the 129S6/SvEvTac (129) strains, plus F1 progeny bred with the previously characterized C57BL/6J (B6) model; F1(BC/B6) or F1(129/B6). By one-month cystic disease in both the BC and 129 Pkd1RC/RC mice was more severe than in B6 and continued with more rapid progression to six to nine months. Thereafter, the expansive disease stage plateaued/declined, coinciding with increased fibrosis and a clear decline in kidney function. Greater severity correlated with more inter-animal and inter-kidney disease variability, especially in the 129-line. Both F1 combinations had intermediate disease severity, more similar to B6 but progressive from one-month of age. Mild biliary dysgenesis, and an early switch from proximal tubule to collecting duct cysts, was seen in all backgrounds. Preclinical testing with a positive control, tolvaptan, employed the F1(129/B6)-Pkd1RC/RC line, which has moderately progressive disease and limited isogenic variability. Magnetic resonance imaging was utilized to randomize animals and provide total kidney volume endpoints; complementing more traditional data. Thus, we show how genetic background can tailor the Pkd1RC/RC model to address different aspects of pathogenesis and disease modification, and describe a possible standardized protocol for preclinical testing.
KW - ADPKD
KW - PKD1
KW - animal models
KW - disease modifiers
KW - preclinical testing
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U2 - 10.1016/j.kint.2021.01.028
DO - 10.1016/j.kint.2021.01.028
M3 - Article
C2 - 33705824
AN - SCOPUS:85105547234
VL - 99
SP - 1392
EP - 1407
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 6
ER -