Protein Composition of Liver Cyst Fluid from the BALB/c-cpk/+ Mouse Model ofAutosomal Recessive Polycystic Kidney Disease (ARPKD)
Ontology highlight
ABSTRACT:
INSTRUMENT(S): instrument model, LTQ
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Liver
DISEASE(S): Polycystic Kidney
SUBMITTER: 
Xianyin Lai
PROVIDER: PRD000807 | Pride | 2009-03-12
REPOSITORIES: Pride
Dataset's files
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| PRIDE_Exp_Complete_Ac_9227.pride.mztab.gz | Mztab | |||
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Publications
Protein composition of liver cyst fluid from the BALB/c-cpk/+ mouse model of autosomal recessive polycystic kidney disease.
Lai Xianyin X Blazer-Yost Bonnie L BL Gattone Vincent H VH Muchatuta Monalisa N MN Witzmann Frank A FA
Proteomics 20090701 14
Cysts arising from hepatic bile ducts are a common extra-renal pathology associated with polycystic kidney disease in humans. As an initial step in identifying active components that could contribute to disease progression, we have investigated the protein composition of hepatic cyst fluid in an orthologous animal model of autosomal recessive polycystic kidney disease, heterozygous (BALB/c-cpk/+) mice. Proteomic analysis of cyst fluid tryptic digests using LC-MS/MS identified 303 proteins, many ...[more]
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Project description:BackgroundA major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation.MethodsWe used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development.ResultsInactivation of Pkhd1 beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of Pkd1, and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression.ConclusionsSomatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1. This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1.
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| S-EPMC5528912 | biostudies-other
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the development of numerous fluid-filled cysts in the kidneys of patients. We recently published our description of the proteome of renal cyst fluid in ADPKD. As a follow-up experiment, we hypothesized that the protein-bound subfraction consists of molecules of mechanistic or diagnostic interest in ADPKD. Using a manual biomarker enrichment kit, we have identified 44 distinct proteins in human cyst fluid.
| S-EPMC2880522 | biostudies-literature
Project description:BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is a rare but potentially lethal genetic disorder typically characterized by diffuse renal microcysts. Clinical trials for patients with ARPKD are not currently possible due to the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy.MethodsIn this study, animal and human magnetic resonance imaging (MRI) scanners were used to obtain quantitative kidney T1 and T2 relaxation time maps for both excised kidneys from bpk and wild-type (WT) mice as well as for a pediatric patient with ARPKD and a healthy adult volunteer.ResultsMean kidney T1 and T2 relaxation times showed significant increases with age (p < 0.05) as well as significant increases in comparison to WT mice (p < 2 × 10-10). Significant or nearly significant linear correlations were observed for mean kidney T1 (p = 0.030) and T2 (p = 0.054) as a function of total kidney volume, respectively. Initial magnetic resonance fingerprinting assessments in a patient with ARPKD showed visible increases in both kidney T1 and T2 in comparison to the healthy volunteer.ConclusionsThese preclinical and initial clinical MRI studies suggest that renal T1 and T2 relaxometry may provide an additional outcome measure to assess cystic kidney disease progression in patients with ARPKD.ImpactA major roadblock for implementing clinical trials in patients with ARPKD is the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy. A clinical need exists to develop a safe and sensitive measure for kidney disease progression, and eventually therapeutic efficacy, for patients with ARPKD. Mean kidney T1 and T2 MRI relaxation times showed significant increases with age (p < 0.05) as well as significant increases in comparison to WT mice (p < 2 ×10-10), indicating that T1 and T2 may provide sensitive assessments of cystic changes associated with progressive ARPKD kidney disease. This preclinical and initial clinical study suggests that MRI-based kidney T1 and T2 mapping could be used as a non-invasive assessment of ARPKD kidney disease progression. These non-invasive, quantitative MRI techniques could eventually be used as an outcome measure for clinical trials evaluating novel therapeutics aimed at limiting or preventing ARPKD kidney disease progression.
| S-EPMC7554096 | biostudies-literature
Project description:Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-? full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-? agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-?, and the number of Ki67- and TGF-?-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.
| S-EPMC3855683 | biostudies-literature
Project description:ObjectiveTo define glomerular filtration rate (GFR) decline, hypertension (HTN), and proteinuria in subjects with autosomal recessive polycystic kidney disease (ARPKD) and compare with 2 congenital kidney disease control groups in the Chronic Kidney Disease in Children cohort.Study designGFR decline (iohexol clearance), rates of HTN (ambulatory/casual blood pressures), antihypertensive medication usage, left ventricular hypertrophy, and proteinuria were analyzed in subjects with ARPKD (n = 22) and 2 control groups: aplastic/hypoplastic/dysplastic disorders (n = 44) and obstructive uropathies (n = 44). Differences between study groups were examined with the Wilcoxon rank sum test.ResultsAnnualized GFR change in subjects with ARPKD was -1.4 mL/min/1.73 m(2) (-6%), with greater decline in subjects age ≥ 10 years (-11.5%). However, overall rates of GFR decline did not differ significantly in subjects with ARPKD vs controls. There were no significant differences in rates of HTN or left ventricular hypertrophy, but subjects with ARPKD had a greater percent on ≥ 3 blood pressure medications (32% vs 0%, P < .0001), more angiotensin-converting enzyme inhibitor use (82% vs 27% vs 36%, P < .0005), and less proteinuria (urine protein: creatinine = 0.1 vs 0.6, P < .005).ConclusionsThis study reports rates of GFR decline, HTN, and proteinuria in a small but well-phenotyped ARPKD cohort. The relatively slow rate of GFR decline in subjects with ARPKD and absence of significant proteinuria suggest that these standard clinical measures may have limited utility in assessing therapeutic interventions and highlight the need for other ARPKD kidney disease progression biomarkers.
| S-EPMC5349855 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in the genes for polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2). Typical onset is in middle age, with gradual replacement of renal tissue with thousands of fluid-filled cysts, resulting in end-stage renal disease requiring dialysis or kidney transplantation. There currently are no approved therapies to slow or cure ADPKD. Mutations in the PKD1 and PKD2 genes abnormally activate multiple signaling proteins and pathways regulating cell proliferation, many of which we observe, through network construction, to be regulated by heat shock protein 90 (HSP90). Inhibiting HSP90 with a small molecule, STA-2842, induces the degradation of many ADPKD-relevant HSP90 client proteins in Pkd1(-/-) primary kidney cells and in vivo. Using a conditional Cre-mediated mouse model to inactivate Pkd1 in vivo, we find that weekly administration of STA-2842 over 10 wk significantly reduces initial formation of renal cysts and kidney growth and slows the progression of these phenotypes in mice with preexisting cysts. These improved disease phenotypes are accompanied by improved indicators of kidney function and reduced expression and activity of HSP90 clients and their effectors, with the degree of inhibition correlating with cystic expansion in individual animals. Pharmacokinetic analysis indicates that HSP90 is overexpressed and HSP90 inhibitors are selectively retained in cystic versus normal kidney tissue, analogous to the situation observed in solid tumors. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.
| S-EPMC3732984 | biostudies-literature
Project description:Background and objectivesWe have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort.Design, setting, participants, and measurementsComprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019.Results and conclusionsOf the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was -1.6 ml/min/1.73 m2/y, in comparison to -0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20-25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the "medullary" to the "corticomedullary" group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
| S-EPMC7749036 | biostudies-literature
Project description:BackgroundMultiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically.MethodsIn this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n?=?20 male/group) using dosages expected to yield clinically relevant drug levels.FindingsCompared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20?mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis.InterpretationSalsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.
| S-EPMC6796518 | biostudies-literature
Project description:Not available
2009-04-30 | PRD000106 | Pride