The role of EGF receptor pathway in ADPKD.

Harskamp, L.R. (Laura) (2013) The role of EGF receptor pathway in ADPKD. thesis, Medicine.

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Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease affecting 1:1000 live births. It is characterized by proliferation of renal tubular cells to form cysts in both kidneys, that progressively expand to cause renal insufficiency. As yet, there is no specific treatment for this disease. It has recently been published that a vasopressin receptor blocker, tolvaptan, slowed the increase in total kidney volume and the decline in kidney function in patients with ADPKD. In normal physiology proliferation of tubular cells is under control of the EGF receptor pathway. In human ADPKD cell lines, an increase in epidermal growth factor receptor (EGFR) expression was observed. However, the EGF receptor ligands expression and concentration have not been measured yet. Therefore, we measured the EGF receptor ligands in ADPKD patients. Methods: In this study 27 ADPKD patients and 27 controls were included. We measured the concentrations of three EGF receptor ligands, HB-EGF, EGF and TGF-α by using commercially available enzyme-linked immunosorbent assays (ELISAs) of which the sensitivity was increased to fit our purpose. In ADPKD patients, the ligands were measured at baseline, three weeks after treatment with tolvaptan and three weeks after wash-out of tolvaptan. Results: Median (interquartile range) HB-EGF excretion were higher in ADPKD patients compared with controls (1851 [1294-2369] ng/24h versus 606 [440-806] ng/24h; P<0.001). In addition, with more disease severity HB-EGF excretion was higher. During treatment with tolvaptan, median (interquartile range) HB-EGF excretion increased even more (2399 [2090-3114] ng/24h; P<0.001). In contrast, median (interquartile range) EGF excretion and TGF-α excretion were lower in ADPKD patients (8784 [1.4-25977] versus 0.2 [0.1-3.5] ng/24h than in controls (32939 [26049-63420] ng/24h versus 3.9 [1.6-6.2] ng/24h; P<0.001). With more disease severity the excretion of EGF and TGF were lower. During treatment, median (interquartile range) TGF-α decreased even more (0.1 [0.08-0.2]; P=0.011). Conclusions: HB-EGF may play a potential role in the pathophysiology of ADPKD. Interestingly, EGF and TGF-α not directly, but they might be down-regulated by HB-EGF. Tolvaptan treatment was associated with an increase in HB-EGF. This may lead to the hypothesis that the renoprotective effect of tolvaptan is counteracted by a negative effect of this drug on HB-EGF concentration.

Item Type:	Thesis (Thesis)
Supervisor name:	Gansevoort, dr. Ron T.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:42
Last Modified:	25 Jun 2020 10:42
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/357

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