TGF-β1 siRNA suppresses the tubulointerstitial fibrosis in the kidney of ureteral obstruction

Hwang, Meeyul; Kim, Hye-Jin; Noh, Hey-Jeong; Chang, Young‐Chae; Chae, Young-Mi; Kim, Kyung-Hyun; Jeon, Jae‐Pil; Lee, Tae-Sung; Oh, Hoon-Kyu; Lee, Yun-Sik; Park, Kwan‐Kyu

doi:10.1016/j.yexmp.2005.11.005

Cited by 67 publications

(57 citation statements)

References 26 publications

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“…37 Many studies have looked for an improvement of renal fibrosis by the inhibition of TGF-␤ signaling. 11 In this study, we found that adenovirus-mediated overexpression of SHP successfully inhibited TGF-␤-stimulated PAI-1 and matrix protein expression in cultured kidney cell lines. Although the mechanism of repression by SHP is not clearly understood, previous reports have suggested that SHP represses transcription factor-mediated transactivation by inhibition of DNA binding, 22,38,39 recruitment of unknown corepressors, 40 -42 and interfering the interaction with coactivator p300.…”

Section: Discussionmentioning

confidence: 62%

“…Thus, suppression of TGF-␤ signaling has been included in several therapeutic approaches for preventing renal fibrosis. 10,11 PAI-1 is the main physiologic inhibitor of the tissue and urokinase plasminogen activator and is considered to be the most important inhibitor of fibrinolysis. 12 However, plasminogen inhibition does not explain the action of PAI-1 in renal fibrosis.…”

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confidence: 99%

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The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Jung¹,

Kim²,

Choe

et al. 2009

Journal of the American Society of Nephrology

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The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-␤ and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-␤ signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral obstruction (UUO) markedly increased the expression of PAI-1, type I collagen, and fibronectin but decreased SHP gene expression. Moreover, in kidneys of SHPϪ/Ϫ mice, the expression of PAI-1, type I collagen, fibronectin and ␣-smooth muscle actin (␣-SMA) were higher compared with those in kidneys of wild-type mice. In addition, loss of SHP accelerated renal fibrosis after UUO. Adenovirus-mediated overexpression of SHP in cultured rat mesangial cells and renal tubular epithelial cells inhibited TGF-␤-stimulated expression of PAI-1, type I collagen, and fibronectin. SHP inhibited TGF-␤-and Smad3-stimulated PAI-1 promoter activities as well as TGF-␤-stimulated binding of Smad3 to its consensus response element on the PAI-1 promoter. Similarly, in vivo, adenovirus-mediated overexpression of SHP in the kidney inhibited the expression of UUO-induced PAI-1, type I collagen, fibronectin, and ␣-SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.

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Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Jung¹,

Kim²,

Choe

et al. 2009

Journal of the American Society of Nephrology

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“…33,34 Previous studies have shown that the inhibition of TGF-b1 attenuates the renal interstitial fibrosis in UUO. 35,36 TGF-b1 mRNA expression in the UUO kidney was not significantly modified by LLLT in this model. Otherwise, this result was …”

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confidence: 59%

Low-Level Laser Therapy Decreases Renal Interstitial Fibrosis

Oliveira

Moraes

Paiva

et al. 2012

Photomedicine and Laser Surgery

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Objective: the purpose of this study was to investigate the effect of low-level laser therapy (LLLT) on chronic kidney disease (CKD) in a model of unilateral ureteral obstruction (UUO). Background data: Regardless of the etiology, CKD involves progressive widespread tissue fibrosis, tubular atrophy, and loss of kidney function. This process also occurs in kidney allograft. At present, effective therapies for this condition are lacking. We investigated the effects of LLLT on the interstitial fibrosis that occurs after experimental UUO in rats. Methods: The occluded kidney of half of the 32 Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm 2 , 30 mW, 0.75 W/cm 2 , 30 sec on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (a-SMA) markers. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the mRNA expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-b1 and Smad3. Results: The UUO and LLLT animals had less fibrosis than the UUO animals, as well having decreased expression inflammatory and pro-fibrotic markers. Conclusions: For the first time, we showed that LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.

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“…In counterpart, favoring the BMP-7 production may generate a cytoprotective state. 10,21,[57][58][59][60][61][62][63][64] This may provide another explanation for the protection observed in PAFR KO mice, since in this group there was a striking reduction in TGF-b/BMP-7 ratio, compared with WT.…”

Section: Pafr and Renal Fibrosismentioning

confidence: 99%

Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

Corrêa-Costa

Andrade-Oliveira

Braga

et al. 2014

Laboratory Investigation

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Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor b (TGF-b) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-b/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.

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TGF-β1 siRNA suppresses the tubulointerstitial fibrosis in the kidney of ureteral obstruction

Cited by 67 publications

References 26 publications

The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Low-Level Laser Therapy Decreases Renal Interstitial Fibrosis

Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

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