Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease

Abstract

Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1-3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1 (lacZ/+) mice, that expressed beta-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1 (lacZ/lacZ) knockout mice. Heterozygous Pkhd1 (lacZ/+) mice expressed beta-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1 (lacZ/lacZ) mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1 (lacZ/lacZ ) mice, with pancreatic cysts arising less frequently. The expression of beta-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1 (lacZ/lacZ ) mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1-3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1 (lacZ/lacZ ) mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.

Loss of Oriented Cell Division Does not Initiate Cyst Formation

“…Pkhd1 del4/del4 mice showed loss of OCD with 58% of tubules (n ϭ 58) having mitotic angles Ͼ30°relative to the luminal vector (median 51°; Figure 1, A and D; Supplemental Videos 1 and 2). Loss of OCD was also apparent in a mouse model of Pkhd1 that forms kidney cysts (Pkhd1 lacZ/lacZ ) 17 with 67% of mitotic angles Ͼ30°(n ϭ 49; median 41°; Supplemental Figure 1). The comparable extent of loss of OCD in Pkhd1 del4/del4 and Pkhd1 lacZ/lacZ mice suggests that absence of cyst formation in Pkhd1 del4/del4 is not the result of a lesser degree of loss of OCD and may, instead, be related to other functional differences between the specific mutant alleles.…”

Effects of hydration in rats and mice with polycystic kidney disease

“…Instead, differences in intrinsic susceptibility to the development of PKD between rats and mice may be a contributory factor. In this regard, it is telling that the PCK rat exhibits renal cysts at or soon after birth (13), whereas most Pkhd1 knockout mice only develop renal cysts at an advanced age or not at all (3,5,6,15,31,32). The renal phenotype of Pkd1 or Pkd2 heterozygous knockout mice is similarly normal or very mild; unfortunately, no Pkd1 or Pkd2 rat model currently exists (21).…”

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

“…12 Likewise, ARPKD patients and mice with cysts not confined to distal tubules and collecting ducts but present in all nephron segments are also known (our unpublished data). 13 Hepatic ductal plate malformation is an invariable feature of ARPKD but can also be found in some patients with ADPKD.…”

“…Williams et al 13 described an ARPKD mouse model with a homozygous Pkhd1 mutation in which Pkd1 and Pkd2 expression was considerably reduced. Direct evidence for genetic interactions between ADPKD and ARPKD loci came from two other mouse studies in which Pkhd1/Pkd1 and Pkhd1/Pkd2 transmutants showed a much more severe renal cystic phenotype than mice bearing a mutation in only one of these genes.…”