Role of genetic modifiers in an orthologous rat model of ARPKD. Physiol Genomics 2012 Aug 01;44(15):741-53
Date
06/07/2012Pubmed ID
22669842Pubmed Central ID
PMC3774585DOI
10.1152/physiolgenomics.00187.2011Scopus ID
2-s2.0-84865616207 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset and severity of the disease. We report here for the first time that ARPKD susceptibility is attenuated by introgressing the mutated Pkhd1 disease allele from the polycystic kidney (PCK) rat onto the FHH (Fawn-Hooded Hypertensive) genetic background. Compared with PCK, the FHH.Pkhd1 strain had significantly decreased renal cyst formation that coincided with a threefold reduction in mean kidney weights. Further analysis revealed that the FHH. Pkhd1 is protected from increased blood pressure as well as elevated plasma creatinine and blood urea nitrogen levels. On the other hand, liver weight and biliary cystogenesis revealed no differences between PCK and FHH.Pkdh1, indicating that genes within the FHH genetic background prevent the development of renal, but not hepatic, manifestations of ARPKD. Microarray expression analysis of kidneys from 30-day-old PCK rats revealed increased expression of genes previously identified in PKD renal expression profiles, such as inflammatory response, extracellular matrix synthesis, and cell proliferation genes among others, whereas the FHH.Pkhd1 did not show activation of these common markers of disease. This newly developed strain can serve as a tool to map modifier genes for renal disease in ARPKD and provides further insight into disease variability and pathophysiology.
Author List
O'Meara CC, Hoffman M, Sweeney WE Jr, Tsaih SW, Xiao B, Jacob HJ, Avner ED, Moreno CAuthors
Ellis D. Avner MD Professor in the Pediatrics department at Medical College of WisconsinCaitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Pressure
Disease Models, Animal
Down-Regulation
Female
Gene Expression Profiling
Gene Regulatory Networks
Genes, Modifier
Humans
Kidney
Kidney Function Tests
Liver
Male
Mutation
Oligonucleotide Array Sequence Analysis
Organ Size
Polycystic Kidney, Autosomal Recessive
Rats
Receptors, Cell Surface
Software
Up-Regulation
