Transforming growth factor-β receptor types I and II are expressed in renal tubules and are increased after chronic unilateral ureteral obstruction

Sutaria, Perry M.; Ohebshalom, Michael; McCaffrey, Timothy A.; Vaughan, E. Darracott; Felsen, Diane

doi:10.1016/s0024-3205(98)00166-0

Cited by 43 publications

(30 citation statements)

References 24 publications

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“…30,31 However, a contribution of tubular epithelial cell injury to ECM accumulation in fibrotic kidneys cannot be excluded. 32,33 To explore the mechanisms by which GQ5 specifically inhibited Smad3 phosphorylation, we examined the effects of GQ5 on the interaction of Smad2/Smad3 with TGF-b receptors, a key event in TGF-b1/Smads activation. Data from coimmunoprecipitation analysis revealed that GQ5 selectively blocked the binding of Smad3 with TbRI without interfering with the Smad2-TbRI interaction.…”

Section: Discussionmentioning

confidence: 99%

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

Nie

et al. 2015

Journal of the American Society of Nephrology

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TGF-b1, via Smad-dependent or Smad-independent signaling, has a central role in the pathogenesis of renal fibrosis. This pathway has been recognized as a potential target for antifibrotic therapy. Here, we identified GQ5, a small molecular phenolic compound isolated from the dried resin of Toxicodendron vernicifluum, as a potent and selective inhibitor of TGF-b1-induced Smad3 phosphorylation. In TGF-b1-stimulated renal tubular epithelial cells and interstitial fibroblast cells, GQ5 inhibited the interaction of Smad3 with TGF-b type I receptor (TbRI) by blocking binding of Smad3 to SARA, suppressed subsequent phosphorylation of Smad3, reduced nuclear translocation of Smad2, Smad3, and Smad4, and downregulated the transcription of major fibrotic genes such as a-smooth muscle actin (a-SMA), collagen I, and fibronectin. Notably, intraperitoneal administration of GQ5 in rats immediately after unilateral ureteral obstruction (UUO) selectively inhibited Smad3 phosphorylation in UUO kidneys, suppressed renal expression of a-SMA, collagen I, and fibronectin, and resulted in impressive renal protection after obstructive injury. Late administration of GQ5 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, our results suggest that GQ5 hinders renal fibrosis in rats by selective inhibition of TGF-b1-induced Smad3 phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

Nie

et al. 2015

Journal of the American Society of Nephrology

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“…However, sustained activation of TGF-␤1 signaling followed by secondary death challenges, a situation that presumably occurs under chronically injured conditions (32), could have lethal consequence to the tubular cells. Our two-hit working model is supported by the in vivo observation that the expression of both TGF-␤1 and its type I receptor is specifically up-regulated in renal tubules of the obstructed kidneys (12,32). Furthermore, this tubulespecific induction of TGF-␤1 axis is an early event that takes place at 1 day after ureteral obstruction (32), a timing that precedes significant cell apoptosis in the kidneys.…”

Section: Discussionmentioning

confidence: 66%

“…Many lines of evidence implicate hyperactive TGF-␤1 as a major pathologic factor in the initiation and progression of chronic renal interstitial fibrosis. Overexpression of TGF-␤1 axis is found in virtually every type of chronic renal diseases in experimental animal models and in patients (12)(13)(14). Inhibition of TGF-␤1 signaling by various strategies prevents renal fibrotic lesions and tubular atrophy and attenuates renal dysfunction (15)(16)(17)(18).…”

mentioning

confidence: 99%

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Dai

Yang

Liu

2003

Journal of Biological Chemistry

137

109

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Tubular atrophy resulting from epithelial cell loss is one of the characteristic features in the development of chronic renal interstitial fibrosis. Although the trigger(s) and mechanism for tubular cell loss remain undefined, the hyperactive transforming growth factor (TGF)-␤1 signaling has long been suspected to play an active role. Here we demonstrate that although TGF-␤1 did not induce cell death per se, it dramatically potentiated renal tubular cell apoptosis initiated by other death cues in vitro. Pre-incubation of human kidney epithelial cells (HKC) with TGF-␤1 markedly promoted staurosporine-induced cell death in a time-and dose-dependent manner. TGF-␤1 dramatically accelerated the cleavage and activation of pro-caspase-9, but not procaspase-8, in HKC cells. This event was followed by an accelerated activation of pro-caspase-3. To elucidate the mechanism underlying TGF-␤1 promotion of tubular cell death, we investigated the signaling pathways activated by TGF-␤1. Both Smad-2 and p38 mitogenactivated protein (MAP) kinase were rapidly activated by TGF-␤1, as demonstrated by the early induction of phosphorylated Smad-2 and p38 MAP kinase, respectively. We found that overexpression of inhibitory Smad-7 completely abolished Smad-2 phosphorylation and activation induced by TGF-␤1 but did not inhibit TGF-␤1-induced apoptosis. However, suppression of p38 MAP kinase with chemical inhibitor SC68376 not only abolished p38 MAP kinase phosphorylation but also obliterated apoptosis induced by TGF-␤1. These results suggest that hyperactive TGF-␤1 signaling potentiates renal tubular epithelial cell apoptosis by a Smadindependent, p38 MAP kinase-dependent mechanism.

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“…TGF-␤ receptors I and II were detected exclusively in renal tubules and were increased in both the obstructed and contralateral kidneys, relative to sham operated animals. 33 Thus the lack of coexpression of endoglin, TGF-␤1, and the receptors I and II might explain the similar extent of renal fibrosis in Eng ϩ/ϩ and Eng ϩ/-mice.…”

Section: Discussionmentioning

confidence: 99%

Endoglin Upregulation During Experimental Renal Interstitial Fibrosis in Mice

et al. 2002

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Abstract-The goal of the present study was to evaluate the role of endoglin, a transforming growth factor-␤1 (TGF-␤1) accessory receptor, in the pathogenesis of renal fibrosis. This was achieved by testing a model of tubulo-interstitial fibrosis induced by unilateral ureteral obstruction in endoglin heterozygous (Eng ϩ/-) mice. Northern and Western blot analysis revealed that endoglin expression in kidneys of these mice was significantly reduced compared with Eng ϩ/ϩ littermates. Pronounced interstitial fibrosis induced by ureteral obstruction was confirmed histologically by Masson's trichromic staining and by increased immunostaining for fibronectin and laminin without significant differences between Eng ϩ/-and Eng ϩ/ϩ mice. Ureteral obstruction induced significant increases in ␣2(I) and ␣1(IV) collagen, fibronectin, and TGF-␤1 mRNA levels, as well as in total kidney collagen but changes were similar in Eng ϩ/-and Eng ϩ/ϩ mouse kidneys. Ureteral obstruction also induced a 2-fold increase in endoglin mRNA levels in both Eng ϩ/ϩ mice and Eng ϩ/-mice, which was confirmed by Western blot analysis. Thus, the present study provides clear evidence that endoglin is upregulated in the kidneys of mice with interstitial fibrosis induced by unilateral ureteral ligation. However, Eng ϩ/-mice do not show any changes in the severity of renal disease induced in this model when compared with normal mice, suggesting that the absolute level of endoglin is not critical for the effects of TGF-␤1 in the renal fibrosis process.

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Transforming growth factor-β receptor types I and II are expressed in renal tubules and are increased after chronic unilateral ureteral obstruction

Cited by 43 publications

References 24 publications

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

Retraction: GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β–Induced Smad3 Phosphorylation

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

Endoglin Upregulation During Experimental Renal Interstitial Fibrosis in Mice

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