Transforming Growth Factor Alpha (TGF-α) and Other Targets of Tumor Necrosis Factor-Alpha Converting Enzyme (TACE) in Murine Polycystic Kidney Disease

Nemo, Raghad; Murcia, Noel S.; Dell, Katherine MacRae

doi:10.1203/01.pdr.0000159513.51898.60

Cited by 27 publications

(23 citation statements)

References 41 publications

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“…29 In addition, increased ErbB4 expression has been shown in a mouse model of autosomal recessive polycystic kidney disease. 7 Of the other ErbBs, deregulated EGFR and ErbB2 signaling has been associated with human autosomal recessive polycystic kidney disease (PKD), 30,31 autosomal dominant PKD, 32,33 and with rodent models of both forms of PKD. 34,35 Furthermore, ErbB2 inhibition reduces cyst formation in a mouse model of PKD and rescues the impaired migration of epithelial cell lines isolated from patients with autosomal dominant PKD.…”

Section: Discussionmentioning

confidence: 99%

“…5 ErbB4 expression is also downregulated in human renal cell carcinoma 6 and is upregulated in a mouse model of autosomal recessive polycystic kidney disease. 7 In this study we addressed the potential role of ErbB4 in mammalian kidney development. We demonstrate that expression of specific Erbb4 isoforms is induced and maintained in the epithelial segments of the kidney, the nephrons, and the collecting ducts.…”

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confidence: 99%

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ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development

Veikkolainen

Naillat

Railo

et al. 2012

Journal of the American Society of Nephrology

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ErbB4 receptor tyrosine kinase contributes to the development of the heart, the central nervous system, and the lactating mammary gland, but whether it has a role in the development of the kidney epithelium is unknown. Here, we found that expression of Erbb4 isoforms JM-a CYT-1 and JM-a CYT-2 was first detectable around embryonic day 13 in the mouse, mainly in the collecting ducts and both the proximal and distal tubules. In vitro, overexpression of a relevant ErbB4 isoform promoted proliferation and disturbed polarization of kidney epithelial cells when cultured as three-dimensional structures. We examined ErbB4 function in developing kidney tubules in vivo with Pax8-Cre-mediated conditional overexpression of Rosa26 locus-targeted ERBB4 and with conditional Erbb4 knock-out mice. The Pax8-Cre-driven ERBB4 overexpression enhanced proliferation in the collecting ducts, reduced the size of epithelial duct lumens, and promoted formation of cortical tubular cysts. These defects were associated with changes in the subcellular distribution of markers of epithelial cell polarity. Similarly, the Pax8-Cre-mediated Erbb4 knock-out mice manifested dysfunctional kidneys with larger duct lumens and epithelial cell mispolarization. Taken together, these data suggest that ErbB4 signaling modulates proliferation and polarization, cellular functions critical for the development of epithelial ducts in the kidney.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development

Veikkolainen

Naillat

Railo

et al. 2012

Journal of the American Society of Nephrology

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“…42 BPK animals were identified using a PCR-based genotyping method that has been described in detail. 43 …”

Section: Bpk Genotypingmentioning

confidence: 99%

Src Inhibition Ameliorates Polycystic Kidney Disease

Sweeney¹,

Vigier²,

Frost³

et al. 2008

Journal of the American Society of Nephrology

150

128

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Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60 c-Src ) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation. With the use of the nonorthologous BPK murine model and the orthologous PCK rat model of ARPKD, greater Src activity was found to correlate with disease progression. Inhibition of Src activity with the pharmacologic inhibitor SKI-606 resulted in amelioration of renal cyst formation and biliary ductal abnormalities in both models. Furthermore, the effects of Src inhibition in PCK kidneys suggest that the ErbB2 and B-Raf/MEK/ERK pathways are involved in Srcmediated signaling in ARPKD and that this occurs without reducing elevated cAMP. These data suggest that Src inhibition may provide therapeutic benefit in PKD.

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“…Accordingly, we previously demonstrated that epiregulin activates EGFR in mouse podocytes while in rat and human mesangial cells HB-EGF serves a similar function (5,7). In PKD, TGF-␣ knockout did not change the rate of cystic growth (16). In bpk mice, increased expression and apical mislocalization of HB-EGF and amphiregulin occur, although the participation of these growth factors in cystic growth is unclear (15).…”

Section: Discussionmentioning

confidence: 98%

“…3). This redundancy in shedded growth factor availability for EGFR activation may explain why knocking down an individual growth factor may not result in decreased cyst growth in PKD (16).…”

Section: Discussionmentioning

confidence: 99%

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

Göõz

Maldonado

Dang

et al. 2014

American Journal of Physiology-Renal Physiology

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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.

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Transforming Growth Factor Alpha (TGF-α) and Other Targets of Tumor Necrosis Factor-Alpha Converting Enzyme (TACE) in Murine Polycystic Kidney Disease

Cited by 27 publications

References 41 publications

ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development

ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development

Src Inhibition Ameliorates Polycystic Kidney Disease

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

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