EGF-related growth factors in the pathogenesis of murine ARPKD

Abstract

Multiple EGF-related growth factors are abnormally expressed in murine ARPKD and may have differential roles in disease pathogenesis. In particular, newly identified abnormalities in heparin-binding EGF expression in cystic kidneys and cells may have important implications for disease pathogenesis.

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

“…In addition, HB-EGF has been reported to play an important role in stimulating cell proliferation of cystic and normal collecting tubular epithelia. 28 Significantly, the HB-EGF expression in affected kidney of Pkd1 L3/L3 mice was found to increase after normalization with ␤-actin expression ( Figure 8A). HB-EGF binds to and activates EGF-receptor (EGFR) with an even greater effect than EGF.…”

Aldosterone as a renal growth factor

“…Silencing of the ARPKD-associated fibrocystin gene in HEK293 cells produced a hyper-proliferative response to EGF and resulted in over-activation of the ERK1/2 cascade following EGF treatment [34]. Over-expression of Heparin-binding EGF is detected in ARPKD and EGF antagonistic antibodies suppress the mitogenic activity of cleared cystic fluid [35]. The abundance of EGFR in cells from the renal tubule is responsive to aldosteronedependent transcription [36] and expression of EGFR is necessary to permit the stimulation of rapid signalling responses by aldosterone in CHO cells [37].…”

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference

“…16,17 Overexpression and apical mislocalization of the epidermal growth factor receptor (EGFR) have been observed in both dominant and recessive forms of human and murine PKD 21 ( Figure). ARPKD cystic epithelia have exhibited EGFR-mediated fluid secretion and proliferation 21 and biliary epithelia in ARPKD/CHF are also hyperresponsive to EGF. 21 The relationship of the polycystin complex to EGFR function has not been satisfactorily elucidated.…”

“…ARPKD cystic epithelia have exhibited EGFR-mediated fluid secretion and proliferation 21 and biliary epithelia in ARPKD/CHF are also hyperresponsive to EGF. 21 The relationship of the polycystin complex to EGFR function has not been satisfactorily elucidated.…”

“…32 EGFR-TKIs, which can be administered orally, have been shown to retard the progression of kidney and liver disease in murine models of ARPKD, reducing renal cyst size and preserving renal function. 21 This class of drugs appears relatively safe in adult patients with cancer; dose-dependent diarrhea and skin rash are the most common side effects. 32 However, the potential side effects of EGFR-TKIs in the pediatric age group are not known.…”