ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease

Abstract

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-α (TGF-α). 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.

Enhanced Proliferation of Porcine Bone Marrow Mesenchymal Stem Cells Induced by Extracellular Calcium is Associated with the Activation of the Calcium‐Sensing Receptor and ERK Signaling Pathway

“…Numerous studies have shown that the activation of the ERK1/2 signaling pathway is involved in regulating the proliferation of various cells, including kidney epithelial cells [ 18 ], smooth muscle cell [ 19 ], melanoma cell [ 20 ], and preadipocytes [ 11 ]. Accordingly, in the present study, the ERK1/2 signaling pathway was activated by [Ca 2+ ] o and the activation of ERK1/2 was abolished by NPS2143.…”

“…The MAPK signaling pathway, which consists of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun kinase (JNK), and p38 MAPK, plays an important role in controlling cell proliferation in mammalian cells [ 17 ]. In particular, ERK1/2 is involved in the proliferation of various cells, such as kidney epithelial cells [ 18 ], smooth muscle cell [ 19 ], melanoma cell [ 20 ], and preadipocytes [ 11 ]. ERK elicits its role in cell proliferation possibly through its effect on the cell cycle transition from the G0/G1 phase to the S phase [ 21 ] and/or on the expression of cyclin D [ 22 , 23 ].…”

Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP‐1–mediated endocytosis

“…Previous studies identified 2 sheddases of LRP-1 in chondrocytes, ADAM-17 and MMP-14 (12). Kidney epithelial cells with the identical IFT88 ORPK mutation have previously been described to have elevated ADAM-17 (45), but, in contrast, we found that IFT88 ORPK chondrocytes expressed similar or lower levels of ADAM-17 than wild-type chondrocytes (Fig. 3B); however, we found increased cellular expression of MMP-14 in IFT88 ORPK chondrocytes compared with wild-type cells (Fig.…”

Involvement of the Warburg effect in non‐tumor diseases processes

“…Besides, Warburg effect accelerates the process of PKD by activating the disintegrin metalloenzyme 17 (ADAM17) (Beck Gooz et al, ). Moreover, ADAM17 can promote proliferation of collecting duct kidney epithelial cells by increasing glycolytic shift via EGFR/MAPK/ERK pathway in PKD cells.…”