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ADAM17 promotes proliferation of collecting duct kidney epithelial cells through
ERK activation and increased glycolysis in polycystic kidney disease
#MMPMID24899059
Beck Gooz M
; Maldonado EN
; Dang Y
; Amria MY
; Higashiyama S
; Abboud HE
; Lemasters JJ
; Bell PD
Am J Physiol Renal Physiol
2014[Sep]; 307
(5
): F551-9
PMID24899059
show ga
Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst
formation in the kidneys and other organs that ultimately results in kidney
failure and death. Currently, there is no therapy for slowing down or stopping
the progression of PKD. In this study, we identified the disintegrin
metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney
tissues of conditional knockout Ift88(-/-) mice and collecting duct epithelial
cells from Ift88°(rpk) mice, animal models of autosomal recessive polycystic
kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a
growth factor-shedding assay in the presence or absence of the specific ADAM17
inhibitor TMI-005, we show that increased expression and activation of ADAM17 in
the cystic kidney and in collecting duct epithelial cells originating from the
Ift88°(rpk) mice (designated as PKD cells) lead to constitutive shedding of
several growth factors, including heparin-binding EGF-like growth factor
(HB-EGF), amphiregulin, and transforming growth factor-? (TGF-?). Increased
growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and
maintains higher cell proliferation rate in PKD cells compared with control
cells. PKD cells also displayed increased lactate formation and extracellular
acidification indicative of aerobic glycolysis (Warburg effect), which was
blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of
cellular proliferation in PKD cells by activating the EGFR/ERK axis and a
proproliferative glycolytic phenotype.
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