Epidermal Growth Factor and Endothelin in Cyst Fluid From Autosomal Dominant Polycystic Kidney Disease Cases: Possible Evidence of Heterogeneity in Cystogenesis

Munemura, Chishio; Uemasu, Jiro; Kawasaki, Hironaka

doi:10.1016/s0272-6386(12)80212-5

Cited by 57 publications

(43 citation statements)

References 26 publications

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“…Two older small scale studies, investigating cystic epithelia of patients with ADPKD, described a modest increase in TGF-a and EGF receptor expression (18,19). Another study described a negative association between EGF concentration in cyst fluid and serum creatinine (20). We found in cyst fluid very low EGF and TGF-a concentrations, whereas HB-EGF was present in a similar concentration range as in plasma, and an increased HB-EGF urinary excretion in patients with ADPKD compared with controls.…”

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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“…In these studies, kidney ET-1 levels were only modestly elevated (two-to three-fold). Elevated concentrations of immunoreactive ET-1 have been found in ADPKD cyst fluid (16) and immunoreactive ET-1 detected in ADPKD cyst epithelium (17). An increase in renal ET-1 gene expression has been documented in two rodent cystic models (18,19).…”

mentioning

confidence: 99%

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Chang¹,

Parker²,

Nahas³

et al. 2007

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2 WS25/؊ ). Four experimental groups (n ‫؍‬ 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD. A utosomal dominant polycystic kidney disease (AD-PKD) causes kidney failure in 10% of all patients who are on renal replacement therapy and is caused by mutations in PKD1 or PKD2 (1). The ADPKD proteins polycystin-1 and polycystin-2 function as a complex and regulate multiple signaling pathways to maintain normal tubular structure and function (2). Although a weak phenotype-genotype correlation for renal survival has been reported for PKD1, it is apparent that nonallelic factors such as genetic modifying loci and/or environmental factors have a greater influence on the cystic phenotype (3,4). These factors probably account for the marked intrafamilial phenotypic variability that sometimes is seen in PKD1 or PKD2 pedigrees (5,6).The endothelins (ET-1, ET-2, and ET-3) are a family of multifunctional peptides with potent effects on BP, renal function, and cellular behavior. Although ET-1 originally was purified as a highly potent endothelial-derived vasoconstrictor (7), many other cell types, especially in the kidney, can synthesize and bind ET-1, suggesting a range of other functions (8,9). Two ET receptor subtypes, ETA and ETB, have been shown to mediate ET-1 action but often with opposing effects (10,11). During development, ET-1 (acting via ETA receptors) and ET-3 (acting via ETB receptors) are essential for the development of neural crest-derived tissues (12,13).Several lines of evidence had suggested that ET-1 might pa...

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“…Other factors proposed to contribute to hypertension in ADPKD include increased sympathetic nerve activity and increased plasma endothelin-1 concentrations [38,39]. AT1 is known to stimulate the pro-fibrogenic cytokine, transforming growth factor beta.…”

Section: Hypertensionmentioning

confidence: 99%

“…This is an important finding as renal interstitial fibrosis is a hallmark of ADPKD. Angiotensin II may also have proliferative effects on tubular epithelial cells via epidermal growth factor (figure 2) [40,41].…”

Section: Hypertensionmentioning

confidence: 99%

“…Aneurysmal rupture carries a 35-55% risk of combined severe morbidity and mortality [66]. RICAs are responsible for 4-7% of deaths in patients with ADPKD and hemorrhage tends to occur at a younger age (mean age of 35-45 years) than in the general population [36,39]. Most patients have normal renal function and up to 29% have normal BP at the time of rupture.…”

Section: Intracranial Aneurysmsmentioning

confidence: 99%

See 1 more Smart Citation

Progress on Autosomal Dominant Polycystic Kidney Disease

Elhassan¹,

Masoumi²,

Schrier³

2010

Arab J. Nephr. Trans

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Epidermal Growth Factor and Endothelin in Cyst Fluid From Autosomal Dominant Polycystic Kidney Disease Cases: Possible Evidence of Heterogeneity in Cystogenesis

Cited by 57 publications

References 26 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

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Progress on Autosomal Dominant Polycystic Kidney Disease

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