Fibroblast autophagy in fibrotic disorders

Principe, Domenico Del; Lista, Pasquale; Malorni, Walter; Giammarioli, Anna Maria

doi:10.1002/path.4115

Cited by 68 publications

(49 citation statements)

References 173 publications

(239 reference statements)

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“…Recent studies implicate dysregulated autophagy in disorders characterized by fibrosis in various tissues, including cardiac fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. 43 We have recently reported a critical role of autophagy in negatively regulating matrix production in glomerular mesangial cells by promoting degradation of intracellular Col-I induced by TGFb1. 28 Moreover, inhibition of autophagy by a selective chemical inhibitor, 3-methyladenine, has been shown to enhance interstitial fibrosis in the obstructed kidneys after UUO in rats.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Ding

Kim

Lee

et al. 2014

Journal of the American Society of Nephrology

223

197

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Autophagy is an evolutionarily conserved process that cells use to degrade and recycle cellular proteins and remove damaged organelles. During the past decade, there has been a growing interest in defining the basic cellular mechanism of autophagy and its roles in health and disease. However, the functional role of autophagy in kidney fibrosis remains poorly understood. Here, using GFP-LC3 transgenic mice, we show that autophagy is induced in renal tubular epithelial cells (RTECs) of obstructed kidneys after unilateral ureteral obstruction (UUO). Deletion of LC3B (LC3 2/2 mice) resulted in increased collagen deposition and increased mature profibrotic factor TGF-b levels in obstructed kidneys. Beclin 1 heterozygous (beclin 1 +/2 ) mice also displayed increased collagen deposition in the obstructed kidneys after UUO. We also show that TGF-b1 induces autophagy in primary mouse RTECs and human renal proximal tubular epithelial (HK-2) cells. LC3 deficiency resulted in increased levels of mature TGF-b in primary RTECs. Under conditions of TGF-b1 stimulation and autoinduction, inhibition of autolysosomal protein degradation by bafilomycin A1 increased mature TGF-b protein levels without alterations in TGF-b1 mRNA. These data suggest a novel intracellular mechanism by which mature TGF-b1 protein levels may be regulated in RTECs through autophagic degradation, which suppresses kidney fibrosis induced by UUO. The dual functions of TGF-b1, as an inducer of TGF-b1 autoinduction and an inducer of autophagy and TGF-b degradation, underscore the multifunctionality of TGF-b1.

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Section: Discussionmentioning

confidence: 99%

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Ding

Kim

Lee

et al. 2014

Journal of the American Society of Nephrology

223

197

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“…Intriguingly, depending on the cell or tissue type and pathological settings, autophagy can be profibrotic or antifibrotic in these organs. [22][23][24][25] For example, autophagy induced in hepatic stellate cells can break down lipids to fuel the activation of these cells to promote liver fibrosis. 26,27 In contrast, autophagy in hepatic macrophages and hepatocytes inhibits inflammation and apoptosis, resulting in the prevention of liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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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“…23 Recent studies have highlighted a correlation between dysregulated autophagy and the development of fibrosis. 24 Both up-and downregulation of autophagy have been associated with fibrosis in various organs, highlighting the potentially diverse functional role that autophagy may play in the various phases of response to stress and tissue repair. 24 In models of liver fibrosis, reduced autophagy was shown to prevent differentiation of hepatic stellate cells into myofibroblast-like cells, therefore leading to reduced fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…24 Both up-and downregulation of autophagy have been associated with fibrosis in various organs, highlighting the potentially diverse functional role that autophagy may play in the various phases of response to stress and tissue repair. 24 In models of liver fibrosis, reduced autophagy was shown to prevent differentiation of hepatic stellate cells into myofibroblast-like cells, therefore leading to reduced fibrogenesis. 25,26 Fibrogenic cells of kidney and lung origin have also been shown to rely on autophagy to maintain an activated and fibrogenic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Autophagy fosters myofibroblast differentiation through MTORC2 activation and downstream upregulation of CTGF

Bernard

Dieudé²,

Yang³

et al. 2014

Autophagy

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Recent evidence suggests that autophagy may favor fibrosis through enhanced differentiation of fibroblasts in myofibroblasts. Here, we sought to characterize the mediators and signaling pathways implicated in autophagy-induced myofibroblast differentiation. Fibroblasts, serum starved for up to 4 d, showed increased LC3-II/-I ratios and decreased SQSTM1/p62 levels. Autophagy was associated with acquisition of markers of myofibroblast differentiation including increased protein levels of ACTA2/aSMA (actin, a 2, smooth muscle, aorta), enhanced gene and protein levels of COL1A1 (collagen, type I, a 1) and COL3A1, and the formation of stress fibers. Inhibiting autophagy with 3 different class I phosphoinositide 3-kinase and class III phosphatidylinositol 3-kinase (PtdIns3K) inhibitors or through ATG7 silencing prevented myofibroblast differentiation. Autophagic fibroblasts showed increased expression and secretion of CTGF (connective tissue growth factor), and CTGF silencing prevented myofibroblast differentiation. Phosphorylation of the MTORC1 target RPS6KB1/p70S6K kinase was abolished in starved fibroblasts. Phosphorylation of AKT at Ser473, a MTORC2 target, was reduced after initiation of starvation but was followed by spontaneous rephosphorylation after 2 d of starvation, suggesting the reactivation of MTORC2 with sustained autophagy. Inhibiting MTORC2 activation with longterm exposure to rapamycin or by silencing RICTOR, a central component of the MTORC2 complex abolished AKT rephosphorylation. Both RICTOR silencing and rapamycin treatment prevented CTGF and ACTA2 upregulation, demonstrating the central role of MTORC2 activation in CTGF induction and myofibroblast differentiation. Finally, inhibition of autophagy with PtdIns3K inhibitors or ATG7 silencing blocked AKT rephosphorylation. Collectively, these results identify autophagy as a novel activator of MTORC2 signaling leading to CTGF induction and myofibroblast differentiation.

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Fibroblast autophagy in fibrotic disorders

Cited by 68 publications

References 173 publications

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

Autophagy Regulates TGF-β Expression and Suppresses Kidney Fibrosis Induced by Unilateral Ureteral Obstruction

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

Autophagy fosters myofibroblast differentiation through MTORC2 activation and downstream upregulation of CTGF

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