Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells

Xu, Yanfang; Yang, Shuyu; Huang, Jian; Shi-wei, Ruan; Zhang, Zheng; Lin, Jiumao

doi:10.3892/ijmm.2012.911

Cited by 62 publications

(68 citation statements)

References 23 publications

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“…35 Later studies further demonstrate autophagy induction by TGFB1 in primary mouse proximal tubular cells and cultured human renal proximal tubular cells. 32,47 Consistently in the current study, autophagy activation by TGFB1 was also shown in both primary culture and cell line of proximal tubular cells (Figs. 8, 10).…”

Section: Discussionsupporting

confidence: 91%

“…34 In addition, TGFB1 induces the upregulation of several autophagy-related genes, such as ATG5, ATG7, and BECN1, in cultured human renal proximal tubular cells. 47 Under this condition, induction of autophagy is associated with an increased generation of reactive oxygen species and enhanced expression of NADPH (reduced NAD phosphate) oxidases. 47 In addition to TGFB1, regulation of autophagy by HIF1A (hypoxia inducible factor 1, a subunit) to activate hepatic stellate cells during liver fibrosis has been suggested recently.…”

Section: Discussionmentioning

confidence: 99%

“…47 Under this condition, induction of autophagy is associated with an increased generation of reactive oxygen species and enhanced expression of NADPH (reduced NAD phosphate) oxidases. 47 In addition to TGFB1, regulation of autophagy by HIF1A (hypoxia inducible factor 1, a subunit) to activate hepatic stellate cells during liver fibrosis has been suggested recently. 48 In the kidney, a role of HIF1A in renal fibrosis has been demonstrated in a mouse model of UUO.…”

Section: Discussionmentioning

confidence: 99%

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Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

et al. 2016

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Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUOassociated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/a-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor b 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

et al. 2016

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“…TGF-␤1 stimulation induced the accumulation of autophagosomes and conversion of LC3 to the lipidated form, LC3-II, and upregulated autophagy-related genes ATG5, ATG7, LC3, and Beclin 1 in renal tubular epithelial cells (19,42,97). We also recently reported that TGF-␤1 induced autophagy in glomerular mesangial cells (18,40).…”

Section: Tgf-␤ Signaling and Autophagymentioning

confidence: 71%

TGF-β signaling in the kidney: profibrotic and protective effects

Sureshbabu

Muhsin

Choi

2016

American Journal of Physiology-Renal Physiology

196

189

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Transforming growth factor-β (TGF-β) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-β and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-β has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-β signaling. Equally, TGF-β signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-β capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-β in promoting not only renal fibrosis but also protective responses of TGF-β signaling. We review, in particular, growing evidence that supports protective effects of TGF-β by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-β actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies.

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“…Production in Human Renal Tubular Endothelial Cells Renal tubular epithelial cells (rTECs) express Noxs, 40,41 including Nox1 and 2, 42,43 and are a target of cell injury driven by O 2 z2 . 3 To determine whether TSP1-SIRP-a-mediated stimulation of O 2 z2 is a general finding and extends to other parenchymal cells, we treated human rTECs with TSP1.…”

Section: ·2mentioning

confidence: 99%

Thrombospondin-1 Activation of Signal-Regulatory Protein-α Stimulates Reactive Oxygen Species Production and Promotes Renal Ischemia Reperfusion Injury

Yao¹,

Rogers²,

Csányi³

et al. 2014

Journal of the American Society of Nephrology

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Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-a (SIRP-a) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-a in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondin-1 and SIRP-a on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-a. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-a and downstream activation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47 phox (an organizer subunit for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1/2) and increased production of superoxide, both of which were abrogated by knockdown or antibody blockade of SIRP-a. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxidemediated vasodilation in a SIRP-a-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-a signaling axis and was associated with increased superoxide production and cell death. A SIRP-a antibody that blocks thrombospondin-1 activation of SIRP-a mitigated the effects of renal IRI, increasing blood flow, suppressing production of reactive oxygen species, and preserving cellular architecture. A role for CD47 in SIRP-a activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-a on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.

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Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells

Cited by 62 publications

References 23 publications

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

TGF-β signaling in the kidney: profibrotic and protective effects

Thrombospondin-1 Activation of Signal-Regulatory Protein-α Stimulates Reactive Oxygen Species Production and Promotes Renal Ischemia Reperfusion Injury

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