Heparin-binding EGF-like growth factor is expressed by mesangial cells and is involved in mesangial proliferation in glomerulonephritis

Takemura, Tamiko; Murata, Yuka; Hino, Shinjiro; Okada, Minoru; Yanagida, Hidehiko; Ikeda, Miyoshi; Yoshioka, Kazuo

doi:10.1002/(sici)1096-9896(199911)189:3<431::aid-path460>3.0.co;2-i

Cited by 31 publications

(27 citation statements)

References 31 publications

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“…Rat podocytes have been reported to show increased HB-EGF protein expression after puromycin aminonucleoside injury in the rat (37). Mesangial cells have EGF receptors and produce HB-EGF, at least in vitro (38,39). Thus, it is possible that transgene expression of hDTR might have some impact on the model even though expression of the transgene in glomeruli was at a low level and did not itself change glomerular structure or function in a measurable way.…”

Section: Discussionmentioning

confidence: 99%

Podocyte Depletion Causes Glomerulosclerosis

Wharram

Goyal

Wiggins³

et al. 2005

Journal of the American Society of Nephrology

675

583

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Glomerular injury and proteinuria in diabetes (types 1 and 2) and IgA nephropathy is related to the degree of podocyte depletion in humans. For determining the causal relationship between podocyte depletion and glomerulosclerosis, a transgenic rat strain in which the human diphtheria toxin receptor is specifically expressed in podocytes was developed. The rodent homologue does not act as a diphtheria toxin (DT) receptor, thereby making rodents resistant to DT. Injection of DT into transgenic rats but not wild-type rats resulted in dose-dependent podocyte depletion from glomeruli. Three stages of glomerular injury caused by podocyte depletion were identified: Stage 1, 0 to 20% depletion showed mesangial expansion, transient proteinuria and normal renal function; stage 2, 21 to 40% depletion showed mesangial expansion, capsular adhesions (synechiae), focal segmental glomerulosclerosis, mild persistent proteinuria, and normal renal function; and stage 3, >40% podocyte depletion showed segmental to global glomerulosclerosis with sustained high-grade proteinuria and reduced renal function. These pathophysiologic consequences of podocyte depletion parallel similar degrees of podocyte depletion, glomerulosclerosis, and proteinuria seen in diabetic glomerulosclerosis. This model system provides strong support for the concept that podocyte depletion could be a major mechanism driving glomerulosclerosis and progressive loss of renal function in human glomerular diseases.

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Section: Discussionmentioning

confidence: 99%

Podocyte Depletion Causes Glomerulosclerosis

Wharram

Goyal

Wiggins³

et al. 2005

Journal of the American Society of Nephrology

675

583

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“…ET-1-stimulated phosphorylation of the EGF-R as well as activation of ERK1/2, and both were attenuated by the EGF-R inhibitor AG-1478. Takemura et al (61) have described the expression of HB-EGF in mesangial cells that was upregulated in experimental glomerulonephritis, a model wherein ERK1/2 is also activated. GPCR-induced transactivation of EGF-R is postulated to be in part mediated through a PKC-dependent mechanism, because the proteolytic cleavage of HB-EGF was shown to be activated by PKC (47).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, a novel mechanism of EGF-R transactivation has been proposed whereby GPCR-mediated activation of Src, PYK2, and Ca 2ϩ mobilization leads to a metalloprotease proteolytic cleavage of the pro-heparinbinding (HB)-EGF precursor to yield the release of a mature ligand, which in turn activates the EGF-R (9, 32). HB-EGF-like growth factor is expressed by mesangial cells and induces cellular proliferation (61). Hence, we postulated that ET-1 signaling and downstream activation of ERK1/2 involves EGF-R transactivation.…”

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confidence: 96%

Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction

Hua

Munk

Whiteside

2003

American Journal of Physiology-Renal Physiology

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Hua, Hong, Snezana Munk, and Catharine I. Whiteside. Endothelin-1 activates mesangial cell ERK1/2 via EGFreceptor transactivation and caveolin-1 interaction. Am J Physiol Renal Physiol 284: F303-F312, 2003. First published September 17, 2002 10.1152/ajprenal.00127.2002.-Endothelin-1 (ET-1) stimulates glomerular mesangial cell proliferation and extracellular matrix protein transcription through an ERK1/2-dependent pathway. In this study, we determined whether ET-1 activation of glomerular mesangial cell ERK1/2 is mediated through EGF receptor (EGF-R) transactivation and whether intact caveolae are required. We showed that ET-1 stimulated tyrosine phosphorylation of the EGF-R in primary cultured, growth-arrested rat mesangial cells. In response to ET-1, ERK1/2 phosphorylation was increased by 27 Ϯ 1-fold and attenuated by AG-1478, a specific EGF-R inhibitor, to 9 Ϯ 1-fold. Moreover, filipin III and ␤-cyclodextrin, two cholesterol-depleting drugs known to disrupt caveolae, significantly reduced ET-1-induced phosphorylation of ERK1/2. In addition, preincubation of mesangial cells with a myristoylated peptide that binds to the caveolin-1 scaffolding domain diminished ET-1 activation of ERK1/2. ET-1 caused interaction of caveolin-1 with phosphorylated ERK1/2 identified by coimmunoprecipitation. Activation of ERK1/2 and its interaction with caveolin-1 were reduced by AG-1478, ␤-cyclodextrin, or inhibition of PKC. Phosphorylated ERK1/2 localized at focal adhesion complexes along with phospho-caveolin-1, suggesting specific sites of compartmentalization of these signaling molecules. Hence, ET-1 activates mesangial cell ERK1/2 predominantly through a pathway involving EGF-R transactivation, leading to a mechanism involving attachment to caveolin-1, presumably in caveolae.caveolae; epidermal growth factor receptor transactivation

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“…HB-EGF has been implicated in the pathogenesis of glomerular injury of diverse etiologies, and increased glomerular HB-EGF expression has been reported in anti-Thy-1.1 mesangial proliferative glomerulonephritis (14,16), acute puromycin aminonucleoside nephrosis (15), passive Heymann nephritis (15), anti-glomerular basement membrane glomerulonephritis (18), and experimental focal glomerular sclerosis (17). A recent study also reported increased glomerular HB-EGF expression in human biopsy material taken from patients with glomerular diseases as diverse as lupus nephritis, membranoproliferative glomerulonephritis, IgA nephropathy, and Schönlein-Henoch purpura (16). In the case of puromycin aminonucleoside nephrosis (15), increased glomerular HB-EGF expression may explain, in part, the increased glomerular HK activity reported by Dubach and Recant in this model over forty years ago (1).…”

Section: Figmentioning

confidence: 99%

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

Robey¹,

Ma²,

Santos³

et al. 2002

Journal of Biological Chemistry

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Heparin-binding epidermal growth factor -like growth factor (HB-EGF) expression and hexokinase (HK) activity are increased in various pathologic renal conditions. Although the mitogenic properties of HB-EGF have been well characterized, its effects on glucose (Glc) metabolism have not. We therefore examined the possibility that HB-EGF might regulate HK activity and expression in glomerular mesangial cells, which constitute the principal renal cell type affected by a variety of pathologic conditions. Protein kinase C (PKC)-dependent classic mitogenactivated protein kinase (MAPK) pathway activation has been associated with increased HK activity in this cell type, so we also examined dependence upon these signaling intermediates. HB-EGF (>10 nM) increased total HK activity over 50% within 12-24 h, an effect mimicked by other EGF receptor agonists, but not by IGF-1 or elevated Glc. EGF receptor and classic MAPK pathway antagonists prevented this increase, as did general inhibitors of gene transcription and protein synthesis. Both HB-EGF and phorbol esters activated the classic MAPK pathway, albeit via PKC-independent and PKC-dependent mechanisms, respectively. Both stimuli were associated with increased HK activity, selectively increased HKII isoform expression, and increased Glc metabolism via both the glycolytic-tricarboxylic acid cycle route and the pentose phosphate pathway. HB-EGF thus constitutes a novel regulator of mesangial cell HK activity and Glc metabolism. HKII is the principal regulated isoform in these cells, as it is in insulin-sensitive peripheral tissues, such as muscle. However, the uniform requirement for classic MAPK pathway activation distinguishes HKII regulation in mesangial cells from that observed in muscle. These findings suggest a novel mechanism whereby growth factors may couple metabolism to glomerular injury.

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Heparin-binding EGF-like growth factor is expressed by mesangial cells and is involved in mesangial proliferation in glomerulonephritis

Cited by 31 publications

References 31 publications

Podocyte Depletion Causes Glomerulosclerosis

Podocyte Depletion Causes Glomerulosclerosis

Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

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