Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1

Jiang, Shinn‐Jong; Chiou, Yuan Yow; Wang, Ellian; Lin, Hsiu Kuan; Lin, Yuan; Chih, Ying; Wang, Chi Kuang Leo; Tang, Ming Jer; Li, Hung

doi:10.2353/ajpath.2006.050342

Cited by 111 publications

(98 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, HB-EGF concentration has not been measured in these previous human studies. In line with our study are the findings in a Pkd1 model showing that the major ligand for the EGF receptor in renal cysts was HB-EGF and not EGF (21). Of note, in the subgroup of patients with ADPKD with normal kidney function (CKD eGFR stages 1 and 2), eGFR was similar as in controls, yet these patients still had significantly higher HB-EGF excretion and decreased TGF-a excretion.…”

Section: Discussionsupporting

confidence: 78%

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Harskamp¹,

Gansevoort²,

Boertien³

et al. 2015

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.Design, setting, participants, & measurements Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-a were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.Results Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, . In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-a did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=20.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-a excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] mg/24 hours; P,0.001).1 ConclusionIn patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.

show abstract

Section: Discussionsupporting

confidence: 78%

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Harskamp¹,

Gansevoort²,

Boertien³

et al. 2015

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…6). Because the ␤2 subunit is highly expressed in normal fetal kidneys (30), this result suggests a degree of either undifferentiation or dedifferentiation in the renal cystic epithelium. Alterations in epithelial cell adhesion and migration also are important characteristics in human and mouse PKD cysts (39).…”

Section: Systemic Manifestation Of the Altered Membrane Proteome Provmentioning

confidence: 83%

“…Using a gene-targeting strategy, we generated PKD1 mutant mice (PKD1 L3/L3 ) with a polycystic kidney phenotype resembling human ADPKD (30). The PKD1 L3/L3 mice appeared normal at birth but developed polycystic kidneys and did not survive past 4 weeks of age (data not shown).…”

Section: Quantitative Analysis Of Membrane Proteins From Kidney Tissumentioning

confidence: 99%

A Multiplexed Quantitative Strategy for Membrane Proteomics

Han

Chien

Chen³

et al. 2008

Molecular & Cellular Proteomics

Self Cite

126

View full text Add to dashboard Cite

Toward multiplexed, comprehensive, and robust quantitation of the membrane proteome, we report a strategy combining gel-assisted digestion, iTRAQ (isobaric tags for relative and absolute quantitation) labeling, and LC-MS/MS. Quantitation of four independently purified membrane fractions from HeLa cells gave high accuracy (<8% error) and precision (<12% relative S.D.), demonstrating a high degree of consistency and reproducibility of this quantitation platform. Under stringent identification criteria (false discovery rate ‫؍‬ 0%), the strategy efficiently quantified membrane proteins; as many as 520 proteins (91%) were membrane proteins, each quantified based on an average of 14.1 peptides per integral membrane protein. In addition to significant improvements in signal intensity for most quantified proteins, most remarkably, topological analysis revealed that the biggest improvement was achieved in detection of transmembrane peptides from integral membrane proteins with up to 19 transmembrane helices. To the best of our knowledge, this level of coverage exceeds that achieved previously using MS and provides superior quantitation accuracy compared with other methods. We applied this approach to the first proteomics delineation of phenotypic expression in a mouse model of autosomal dominant polycystic kidney disease (ADPKD). By characterizing kidney cell plasma membrane from wild-type versus PKD1 knock-out mice, 791 proteins were quantified, and 67 and 37 proteins showed >2-fold up-regulation and down-regulation, respectively. Some of these differentially expressed membrane proteins are involved in the mechanisms underlying major abnormalities in ADPKD, including epithelial cell proliferation and apoptosis, cell-cell and cell-matrix interactions, ion and fluid secretion, and membrane protein polarity. Among these proteins, targeting therapeutics to certain transporters/receptors, such as epidermal growth factor receptor, has proven effective in preclinical studies of ADPKD; others are known drug targets in various diseases. Our method demonstrates how comparative membrane proteomics can provide insight into the molecular mechanisms underlying ADPKD and the identification of potential drug targets, which may lead to new therapeutic opportunities to prevent or retard the disease.

show abstract

“…These cysts were only observed in Pkd1 knock-out mice but not in hypomorphic mice that have low levels of Pkd1 gene expression, suggesting that total absence of Pkd1 is necessary to induce the formation of glomerular cysts. 10,11,15,17,43,44 How these cysts arise is not entirely clear. As Pkd1 is deleted in Bowman's capsule, the suggested mechanism that urinary tract infections lead to increased pressure in Bowman's space seems not very likely in SM22-Pkd1 del/del mice.…”

Section: Discussionmentioning

confidence: 99%

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

Hassane¹,

Claij²,

Jodar³

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by renal, hepatic and pancreatic cyst formation and cardiovascular complications. The condition is caused by mutations in the PKD1 or PKD2 gene. In mice with reduced expression of Pkd1, dissecting aneurysms with prominent media thickening have been seen. To study the effect of selective disruption of Pkd1 in vascular smooth muscle cells (SMCs), we have generated mice in which a floxed part of the Pkd1 gene was deleted by Cre under the control of the SM22 promotor (SM22-Pkd1 del/del mice). Cre activity was confirmed by X-gal staining using lacZ expressing Cre reporter mice (R26R), and quantitative PCR indicated that in the aorta Pkd1 gene expression was strongly reduced, whereas Pkd2 levels remained unaltered. Histopathological analysis revealed cyst formation in pancreas, liver and kidneys as the result of extravascular Cre activity in pancreatic ducts, bile ducts and in the glomerular Bowman's capsule. Remarkably, we did not find any spontaneous gross structural blood vessel abnormalities in mice with somatic Pkd1 gene disruption in SMCs or simultaneous disruption of Pkd1 in SMCs and endothelial cells (ECs). Extensive isometric myographic analysis of the aorta did not reveal differences in response to KCl, acetylcholine, phenylephrin or serotonin, except for a significant increase in contractility induced by phenylephrin on arteries from 40 weeks old Pkd1 del/ þ germ-line mice. However, SM22-Pkd1 del/del mice showed significantly reduced decrease in heart rate on angiotensin II-induced hypertension. The present findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1 del/del mice.

show abstract

Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1

Cited by 111 publications

References 46 publications

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

A Multiplexed Quantitative Strategy for Membrane Proteomics

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

Contact Info

Product

Resources

About