An integrative view on the role of TGF-β in the progressive tubular deletion associated with chronic kidney disease

García-Sánchez, Omar; López‐Hernández, Francisco J.; López‐Novoa, José M.

doi:10.1038/ki.2010.88

Cited by 137 publications

(129 citation statements)

References 43 publications

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“…43 Autophagy is induced by TGFB1 in BUMPT mouse proximal tubular cell line along with profibrotic changes TGFB1 is induced in proximal tubules following renal injury and plays a central role in mediating renal interstitial fibrosis. 44 In the current study, TGFB1 was activated and increased in mouse kidneys following UUO (Fig. S1).…”

Section: Autophagy Is Persistently Induced In Kidney Proximal Tubulesmentioning

confidence: 94%

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: Autophagy Is Persistently Induced In Kidney Proximal Tubulesmentioning

confidence: 94%

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

et al. 2016

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“…Next, the activation of interstitial cells, which are responsible for ECM deposition in tubulointerstitial fibrosis (Alpers et al, 1994;Remuzzi and Bertani, 1998;Garcia-Sanchez et al, 2010), may derived in part from the transition of tubular epithelial cells to myofibroblasts (Fan et al, 1999;Iwano et al, 2002) and activation of interstitial fibroblasts (Alpers et al, 1994;Grupp et al, 1997). During renal fibrosis, tubular epithelial cells acquire myofibroblast characteristics and interstitial fibroblast activation.…”

Section: Figurementioning

confidence: 99%

Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro‐inflammatory factors in vivo and in vitro

Chiang

Sheu

Lin

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSE Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. The present study investigated, in vivo and in vitro, the anti-fibrotic and anti-inflammatory effects, particularly on the epithelial to mesenchymal transition of renal tubular cells, exerted by honokiol, a phytochemical used in traditional medicine, and mechanisms underlying these effects. EXPERIMENTAL APPROACH Anti-fibrotic effects in vivo were assayed in a rat model of renal fibrosis [the unilateral ureteral obstruction (UUO) model]. A rat tubular epithelial cell line (NRK-52E) was stimulated by transforming growth factor-beta 1 (TGF-beta 1) and treated with honokiol to explore possible mechanisms of these anti-fibrotic effects. Gene or protein expression was analysed by Northern or Western blotting. Transcriptional regulation was investigated using luciferase activity driven by a connective tissue growth factor (CTGF) promoter. KEY RESULTS Honokiol slowed development of renal fibrosis both in vivo and in vitro. Honokiol treatment attenuated tubulointerstitial fibrosis and expression of pro-fibrotic factors in the UUO model. Honokiol also decreased expression of the mRNA for the chemokine CCL2 and for the intracellular adhesion molecule-1, as well as accumulation of type I (alpha 1) collagen and fibronectin in UUO kidneys. Phosphorylation of Smad-2/3 induced by TGF-beta 1 and CTGF luciferase activity in renal tubular cells were also inhibited by honokiol. CONCLUSIONS AND IMPLICATIONS Honokiol suppressed expression of pro-fibrotic and pro-inflammatory factors and of extracellular matrix proteins. Honokiol may become a therapeutic agent to prevent renal fibrosis

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“…14,15 Binding of TGF-b1 to its receptors induces the phosphorylation of Smad2/3, which allows them to regulate the transcription of target genes. 16 When TGF-b1 stimulation is terminated, Smad2/3 becomes dephosphorylated.…”

mentioning

confidence: 99%

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

Inoue

Matsui

Hamano

et al. 2012

Laboratory Investigation

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Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-b1 (TGF-b1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-b1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-b1, pSmad3 bound to the proximal promoter region of the TGF-b1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-b1 increased both the nuclear levels of protein phosphatase Mg 2 þ /Mn 2 þ -dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-b1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-b1. Our findings provide a novel approach to inhibit the TGF-b pathway in fibrotic diseases. Tubulointerstitial fibrosis (TIF) is the final common pathway for most forms of progressive kidney diseases. 1-3 Numerous studies revealed that two major signaling pathways, the renin-angiotensin system (RAS) and the transforming growth factor-b1 (TGF-b1)/Smad system, have important roles in the pathogenesis of TIF. [3][4][5][6] However, because satisfactory therapeutic strategies have not been established, TIF remains one of the major problems in nephrology.One of the candidates that protect the kidney from TIF is active vitamin D because it is a negative regulator of renin. 7,8 Several lines of studies revealed the renin-suppressive effect of 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. [9][10][11][12] In addition to 1,25(OH) 2 D, a less-calcemic analog, paricalcitol, has been revealed to suppress renin in the kidney. 13 These findings provide a rationale for active vitamin D therapy in renal diseases with high local renin.

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An integrative view on the role of TGF-β in the progressive tubular deletion associated with chronic kidney disease

Cited by 137 publications

References 43 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

Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro‐inflammatory factors in vivo and in vitro

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

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