Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher, Anna-Rachel; Esquivel, Ernie; Briere, Tiffany S.; Tian, Xin; Mitobe, Michihiro; Menezes, Luís F.; Markowitz, Glen S.; Jain, Dhanpat; Onuchic, Luiz Fernando; Somlo, Stefan

doi:10.2353/ajpath.2008.070381

Cited by 77 publications

(81 citation statements)

References 46 publications

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“…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).…”

Section: Pkd2mentioning

confidence: 94%

Effects of hydration in rats and mice with polycystic kidney disease

Hopp

Wang

et al. 2015

American Journal of Physiology-Renal Physiology

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Hopp K, Wang X, Ye H, Irazabal MV, Harris PC, Torres VE. Effects of hydration in rats and mice with polycystic kidney disease. Am J Physiol Renal Physiol 308: F261-F266, 2015. First published December 10, 2014 doi:10.1152/ajprenal.00345.2014.-Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C (Pkd1 RC/RC ) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1 RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-D-arginine vasopressin, as previously shown for Pkd1 RC/RC mice and confirmed here in Pkd2 WS25/Ϫ mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models. polycystic kidney disease; vasopressin; cAMP; cyclic nucleotide phosphodiesterase; hydration POLYCYSTIC KIDNEY DISEASES (PKDs) are characterized by the development and growth of cysts arising from renal tubules and associated with enlargement of the kidneys and destruction of the renal parenchyma. Autosomal dominant PKD (AD-PKD), the fourth leading cause of end-stage kidney disease in adults, is caused by mutations to either of two genes, PKD1 or PKD2. Autosomal recessive PKD (ARPKD), an important cause of end-stage renal disease and mortality in infants and children, is caused by mutations to polycystic kidney and hepatic disease 1 (PKHD1) (9,23).A large body of evidence indicates that vasopressin and V2 receptor signaling promote the progression of PKD via cAMP and PKA (22). Administration of the V2 receptor agonist 1-deamino-8-D-arginine vasopressin (DDAVP) aggravates the disease in orthologous models of ARPKD and PKD1 (10,28). Genetic elimination of circulating vasopressin markedly inhibits the development of PKD in PCK rats, an effect that was reversed by the administration of DDAVP (28). Treatment with select...

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Section: Pkd2mentioning

confidence: 94%

Effects of hydration in rats and mice with polycystic kidney disease

Hopp

Wang

et al. 2015

American Journal of Physiology-Renal Physiology

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“…13 We sought to determine whether similar loss of OCD occurs in the Pkhd1 del4/del4 mouse model, which does not develop cystic kidneys. 16 Mitotic spindles of dividing cells in Pkhd1 del4/del4 mice at postnatal days 7 to 10 (P7 to P10) were marked with antiphosphorylated Ser10 in histone H3 (anti-H3pS10), and the angle of the spindle poles relative to unambiguous luminal vector of medullary collecting tubules was measured. 13 In kidneys from wildtype (WT) mice, OCD was evidenced with 92% of mitotic angles (n ϭ 48) deviating Ͻ30°from the vector of the tubule lumen (median 6°; Figure 1D).…”

Section: Mutations In Pkhd1mentioning

confidence: 99%

“…We quantified apoptosis by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining in collecting duct segments marked by Dolichos biflorus agglutinin that express fibrocystin 16 and show loss of OCD.…”

Section: Pkhd1mentioning

confidence: 99%

“…By contrast, our Pkhd1 del4 model of recessive PKD, like its rat ortholog, 13 showed loss of OCD but, unlike the rat model, did not develop kidney cysts. 16 The normal-appearing tubule morphology in Pkhd1 del4/del4 is maintained by increased intercalation of cells into the plane of the epithelium that is associated with a small but significant increase in the number of cells present in transverse tubular profiles. Pkhd1 functions in a PCP pathway to maintain OCD.…”

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confidence: 99%

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Loss of Oriented Cell Division Does not Initiate Cyst Formation

Nishio¹,

Tian²,

Gallagher³

et al. 2010

Journal of the American Society of Nephrology

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Polycystic kidney disease (PKD) can arise from either developmental or postdevelopmental processes. Recessive PKD, caused by mutations in PKHD1, is a developmental defect, whereas dominant PKD, caused by mutations in PKD1 or PKD2, occurs by a cellular recessive mechanism in mature kidneys. Oriented cell division is a feature of planar cell polarity that describes the orientation of the mitotic axes of dividing cells during development with respect to the luminal vector of the elongating nephron. In polycystic mutant mice, the loss of oriented cell division may also contribute to the pathogenesis of PKD. Here, we examined the role of oriented cell division in mouse models based on mutations in Pkd1, Pkd2, and Pkhd1. Precystic tubules after kidney-selective inactivation of either Pkd1 or Pkd2 did not lose oriented division before cystic dilation but lost oriented division after tubular dilation began. In contrast, Pkhd1 del4/del4 mice lost oriented cell division but did not develop kidney cysts. Increased intercalation of cells into the plane of the tubular epithelium maintained the normal tubular morphology in Pkhd1 del4/del4 mice, which had more cells present in transverse tubular profiles. In conclusion, loss of oriented cell division is a feature of Pkhd1 mutation and cyst formation, but it is neither sufficient to produce kidney cysts nor required to initiate cyst formation after mutation in Pkd1 or Pkd2.

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“…13 It is expressed predominantly in the kidney (mostly in collecting ducts and thick ascending loops of Henle), liver (in bile duct epithelia), and pancreas. 11,[13][14][15] In renal tubular and biliary epithelial cells, FPC localizes to apical membranes, the primary cilia/basal body, 13,14,[16][17][18][19] and mitotic spindle. 20 The exact function of FPC remains unclear.…”

Section: Genetics Of Arpkd Background Of the Gene And Proteinmentioning

confidence: 99%

Autosomal Recessive Polycystic Kidney Disease: A Hepatorenal Fibrocystic Disorder With Pleiotropic Effects

2014

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Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of chronic kidney disease in children. The care of ARPKD patients has traditionally been the realm of pediatric nephrologists; however, the disease has multisystem effects, and a comprehensive care strategy often requires a multidisciplinary team. Most notably, ARPKD patients have congenital hepatic fibrosis, which can lead to portal hypertension, requiring close follow-up by pediatric gastroenterologists. In severely affected infants, the diagnosis is often first suspected by obstetricians detecting enlarged, echogenic kidneys and oligohydramnios on prenatal ultrasounds. Neonatologists are central to the care of these infants, who may have respiratory compromise due to pulmonary hypoplasia and massively enlarged kidneys. Surgical considerations can include the possibility of nephrectomy to relieve mass effect, placement of dialysis access, and kidney and/or liver transplantation. Families of patients with ARPKD also face decisions regarding genetic testing of affected children, testing of asymptomatic siblings, or consideration of preimplantation genetic diagnosis for future pregnancies. They may therefore interface with genetic counselors, geneticists, and reproductive endocrinologists. Children with ARPKD may also be at risk for neurocognitive dysfunction and may require neuropsychological referral. The care of patients and families affected by ARPKD is therefore a multidisciplinary effort, and the general pediatrician can play a central role in this complex web of care. In this review, we outline the spectrum of clinical manifestations of ARPKD and review genetics of the disease, clinical and genetic diagnosis, perinatal management, management of organ-specific complications, and future directions for disease monitoring and potential therapies.

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Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Cited by 77 publications

References 46 publications

Effects of hydration in rats and mice with polycystic kidney disease

Effects of hydration in rats and mice with polycystic kidney disease

Loss of Oriented Cell Division Does not Initiate Cyst Formation

Autosomal Recessive Polycystic Kidney Disease: A Hepatorenal Fibrocystic Disorder With Pleiotropic Effects

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