Autocrine production and TGF-beta 1-mediated effects on metabolism and viability in renal cells

Nowak, Grażyna; Schnellmann, Rick G.

doi:10.1152/ajprenal.1996.271.3.f689

Cited by 31 publications

(34 citation statements)

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“…Previous studies indicate that RPTC produce TGF-␤ after oxidant injury, and at a concentration of 0.2 ng/ml exogenous TGF-␤ 1 induces glycolytic metabolism, decreased Na ϩ /K ϩ ATPase activity, and cell rounding and detachment (Nowak and Schnellmann, 1996a;Nowak and Schnellmann, 1997). Whereas the current experiments revealed that exogenous TGF-␤ enhances dedifferentiation, TGF-␤ receptor inhibition had no effect on redifferentiation.…”

Section: Discussioncontrasting

confidence: 67%

Regulation of Dedifferentiation and Redifferentiation in Renal Proximal Tubular Cells by the Epidermal Growth Factor Receptor

Hallman

Zhuang²,

Schnellmann³

2008

J Pharmacol Exp Ther

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Repair of injured renal epithelium is thought to be mediated by surviving renal proximal tubular cells (RPTC) that must dedifferentiate to allow the proliferation and migration necessary for epithelial regeneration. RPTC then redifferentiate to restore tubular structure and function. Current models suggest that epidermal growth factor receptor (EGFR) activation is required for dedifferentiation characterized by enhanced vimentin expression, decreased N-cadherin expression, spindle morphology, and loss of apical-basal polarity after injury. Because an in vitro model of RPTC redifferentiation has not been reported, and the mechanism(s) of redifferentiation has not been determined, we used rabbit RPTC in primary cultures to address these issues. H 2 O 2 induced the dedifferentiated phenotype that persisted Ͼ48 h; redifferentiation occurred spontaneously in the absence of exogenous growth factors after 72 to 120 h.Phosphorylation of two tyrosine residues of EGFR increased 12 to 24 h, peaked at 24 h, and declined to basal levels by 48 h after injury. EGFR inhibition during dedifferentiation restored epithelial morphology and apical-basal polarity, and it decreased vimentin expression to control levels 24 h later. In contrast, exogenous epidermal growth factor addition increased vimentin expression and potentiated spindle morphology. p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-␤ receptor inhibitors did not affect redifferentiation after H 2 O 2 injury. Similar results were observed in a mechanical injury model. These experiments represent a new model for the investigation of RPTC redifferentiation after acute injury and identify a key regulator of redifferentiation: EGFR, independent of p38 MAPK and the TGF-␤ receptor.The physiologic role of renal proximal tubular cells (RPTC) engenders their susceptibility to ischemic and toxic injury. However, the proximal tubular epithelium is capable of regeneration, and full recovery is often observed (Cuppage et al., 1972;Houghton et al., 1976). Regeneration is initiated when surviving RPTC sequentially dedifferentiate, migrate, and proliferate to restore monolayer confluence (Toback, 1992;Toback et al., 1993;Abbate and Remuzzi, 1996;Molitoris and Marrs, 1999). Finally, regenerated cells redifferentiate to restore RPTC function and structure (Nony and Schnellmann, 2003;Rasbach and Schnellmann, 2007).After RPTC injury, dedifferentiation and redifferentiation processes resemble epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition, respectively (Brabletz et al., 2005;Zhuang et al., 2005). The terms EMT and mesenchymal-epithelial transition indicate the direction of transdifferentiation of cells between the epithelial and mesenchymal phenotypes (Brabletz et al., 2005). RPTC are columnar and cuboidal in nature, with adherens junctions that contain, in part, N-cadherin, which are supported by cortical actin rings and contribute to apical-basal polarity (Takeichi, 1991;Prozialeck et al., 2004). During dedifferentiati...

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Section: Discussioncontrasting

confidence: 67%

Regulation of Dedifferentiation and Redifferentiation in Renal Proximal Tubular Cells by the Epidermal Growth Factor Receptor

Hallman

Zhuang²,

Schnellmann³

2008

J Pharmacol Exp Ther

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“…In contrast to the paucity of literature on TGF-b and tubular apoptosis in AKI, many reports have described TGF-b's proapoptotic effect on renal tubular cells in vitro. 13,14,35,36 The reduced Smad signaling in proximal tubules lacking TbRII in vivo and in vitro suggests that reduced Smad signaling protects against apoptosis, and this was confirmed with siRNA studies. Smad2/3 signaling may augment apoptosis by altering cell cycle repressor elements or reducing the antiapoptotic protein Bcl-2.…”

Section: Discussionmentioning

confidence: 67%

Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

Gewin

Vadivelu²,

Neelisetty³

et al. 2012

Journal of the American Society of Nephrology

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TGF-b is a profibrotic growth factor in CKD, but its role in modulating the kidney's response to AKI is not well understood. The proximal tubule epithelial cell, which is the main cellular target of AKI, expresses high levels of both TGF-b and its receptors. To determine how TGF-b signaling in this tubular segment affects the response to AKI, we selectively deleted the TGF-b type II receptor in the proximal tubules of mice. This deletion attenuated renal impairment and reduced tubular apoptosis in mercuric chloride-induced injury. In vitro, deficiency of the TGF-b type II receptor protected proximal tubule epithelial cells from hydrogen peroxide-induced apoptosis, which was mediated in part by Smad-dependent signaling. Taken together, these results suggest that TGF-b signaling in the proximal tubule has a detrimental effect on the response to AKI as a result of its proapoptotic effects.

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“…These proteinases include matrix metalloproteinases/tissue inhibitors of metalloproteinases, and plasminogen activators/plasminogen activator inhibitors (Gong et al, 2003;Mizuno et al, 2000). TGF-β1 induces growth arrest and apoptosis in renal tubular cells and endothelial cells (Nowak and Schnellmann, 1996;, while HGF exhibits mitogenic, motogenic, morphogenic, and anti-apoptotic activities in these cell types (Bowes et al, 1999;Dai et al, 2004;Liu, 1999). Furthermore, the epithelial to myofibroblast transition can be induced by TGF-β1 and reversed by HGF (Blobe et al, 2000;Fan et al, 1999;.…”

Section: Discussionmentioning

confidence: 99%

Astragalus mongholicus ameliorates renal fibrosis by modulating HGF and TGF-β in rats with unilateral ureteral obstruction

Zuo

Xie

Qiu

et al. 2009

J. Zhejiang Univ. Sci. B

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Abstract:Astragalus mongholicus (AM) derived from the dry root of Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao is a widely used traditional Chinese medicine. The present study investigated the potential role of AM on renal fibrosis on a rat model of unilateral ureteral obstruction (UUO). We divided 48 Sprague-Dawley rats randomly into 4 groups: sham-operated group (Sham), untreated UUO group, AM-treated (10 g/(kg·d)) UUO group, and losartan-treated (20 mg/(kg·d)) UUO group as positive control. Haematoxylin & eosin (HE) and Masson staining were used to study the dynamic histological changes of the kidneys 7 and 14 d after operation. The expressions of fibronectin (FN), type I collagen (colI), hepatocyte growth factor (HGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA) were analyzed by real-time polymerase chain reaction (PCR), immunohistochemistry staining, and Western blot. Results show that, similar to losartan, AM alleviated the renal damage and decreased the deposition of FN and colI from UUO by reducing the expressions of TGF-β1 and α-SMA (P<0.05), whereas HGF increased greatly with AM treatment (P<0.05). Our findings reveal that AM could retard the progression of renal fibrosis. The renoprotective effect of AM might be related to inhibition of myofibroblast activation, inducing of HGF and reducing of TGF-β1 expression.

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Autocrine production and TGF-beta 1-mediated effects on metabolism and viability in renal cells

Cited by 31 publications

References 0 publications

Regulation of Dedifferentiation and Redifferentiation in Renal Proximal Tubular Cells by the Epidermal Growth Factor Receptor

Regulation of Dedifferentiation and Redifferentiation in Renal Proximal Tubular Cells by the Epidermal Growth Factor Receptor

Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

Astragalus mongholicus ameliorates renal fibrosis by modulating HGF and TGF-β in rats with unilateral ureteral obstruction

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