Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys

Yamaguchi, Tomohiro; Nagao, Shizuko; Wallace, Darren P.; Belibi, Franck A.; Cowley, Benjamin D.; Pelling, Jill C.; Grantham, Jared J.

doi:10.1046/j.1523-1755.2003.00023.x

Cited by 297 publications

(303 citation statements)

References 34 publications

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“…First, vasopressin stimulates intracellular cAMP production in collecting duct cells. Both cAMP and EGF receptor activation stimulate the proliferation of tubular cells to form cysts by the RAS/RAF/MEK/ERK pathway (23). Cross-talk between these two pathways could exist (i.e., between the EGF receptor and the vasopressin-cAMP pathways [24][25][26]), resulting in an increase in HB-EGF during treatment with the V2RA.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…20 There are higher cAMP levels in cholangiocytes of ADPKD rodent models, which is associated with cholangiocyte hyperproliferation and cyst expansion. 21,22 …”

Section: Clinical Presentation and Epidemiologymentioning

confidence: 99%

Medical and surgical treatment options for polycystic liver disease1

et al. 2010

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“…cAMP accumulation and Ser/Thr kinase mammalian target of rapamycin (mTOR) activation mediate cyst expansion (2)(3)(4)(5), whereas mTOR inhibition with sirolimus or everolimus slowed cyst growth and preserved renal function in a variety of animal models of polycystic kidney disease (4,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

Ruggenenti

Gentile

Perico

et al. 2016

CJASN

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Background and objectives The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.Design, setting, participants, & measurements In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria #0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.Results At the 1-year preplanned interim analysis, GFR fell from 26.765.8 to 21.366.3 ml/min per 1.73 m 2 (P,0.001) and from 29.665.6 to 24.966.2 ml/min per 1.73 m 2 (P,0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8681.8 versus 154.96152.9 mg/min; P=0.02) and proteinuria (0.360.2 versus 0660.4 g/24 h; P,0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P,0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrastenhanced computed tomography imaging) increased by 9.0% from 2857.761447.3 to 3094.661519.5 ml on sirolimus and 4.3% from 3123.461695.3 to 3222.661651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.Conclusions Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

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Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys

Cited by 297 publications

References 34 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

Medical and surgical treatment options for polycystic liver disease1

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4

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