Defects of renal tubular homeostasis and cystogenesis in the Pkhd1 knockout

Loss of PKHD1-gene function causes autosomal recessive polycystic kidney disease (ARPKD) characterized by bilateral severely enlarged kidneys and congenital liver fibrosis requiring kidney replacement therapy most frequently during childhood. Studies using renal tissue from ARPKD patients suggest cyst promotion by suppressed hippo activity and enhanced Src/STAT3-signaling. We address renal homeostasis in female Pkhd1-knockout mice, aged 3 to 9 months, and observe features in common with late-onset ARPKD. Pkhd1-knockout animals show significant increase in kidney and liver weight with preserved organ function. Kidney cyst formation of the S3 segment is accompanied by macrophage recruitment and fibrotic remodeling. Cystic epithelia display increased proliferation, high levels of nuclear YAP/TAZ, and enhanced apoptosis. Y705-phosphorylated STAT3 is strongly enhanced in nuclei of cyst-lining epithelia. In this Pkhd1-deficiency model, stressed cystic epithelia expose the altered signaling pattern and disease-related mechanisms deemed relevant to human ARPKD, and thus may allow identification of therapeutic targets of this disease.