Experimental Inhibition of Periostin Attenuates Kidney Fibrosis

Hwang, Jin Ho; Yang, Seung Hee; Kim, Yong Chul; Kim, Jin‐Hyuk; An, Jung Nam; Moon, Kyung Chul; Oh, Yun Kyu; Park, Sun-Hee; Kim, Yon Su; Lim, Chun Soo; Lee, Jung Pyo

doi:10.1159/000485325

Cited by 26 publications

(31 citation statements)

References 42 publications

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“…The mRNA expression of periostin after p38 MAPK inhibition showed only a tendency to decrease. Periostin is known to play an important role in kidney fibrosis [37,38]. This finding might suggest that a p38 MAPK independent pathway involving periostin, such as the TGF-β/Smad pathway, could contribute to the development of kidney fibrosis [39–41].…”

Section: Discussionmentioning

confidence: 99%

p38 MAPK activity is associated with the histological degree of interstitial fibrosis in IgA nephropathy patients

Lee

Hwang

et al. 2019

PLoS ONE

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Activation of p38 mitogen-activated protein kinase (MAPK) is associated with tissue fibrosis, and inhibition of p38 MAPK can attenuate the progression of fibrosis. We aimed to investigate whether p38 MAPK activity in kidney tissue confirmed by immunohistochemical staining is associated with renal tubulointerstitial fibrosis in chronic kidney disease patients with IgA nephropathy. We collected kidney biopsy specimens from 341 IgA nephropathy patients and 15 control patients to identify the clinical and histopathological factors associated with kidney tubulointerstitial fibrosis and to find an association between kidney phosphorylated p38 immunoactivity and pathological grading. In addition, we aimed to investigate whether the anti-fibrotic effect of p38 MAPK inhibition can be identified by assessing the immunostaining intensity of phosphorylated p38 in kidney tissue. A renal tubulointerstitial fibrosis model was introduced using 7-week-old C57BL/6 mice subjected to unilateral ureteral obstruction (UUO). The p38 MAPK inhibitor SB-731445 was injected intraperitoneally every day for 7 days, and changes in renal fibrosis-associated markers were investigated. Assessment of kidney biopsy specimens from IgA nephropathy patients revealed that the degree of interstitial fibrosis was significantly associated with the tissue immunoactivity of phosphorylated p38. High-grade interstitial fibrosis was associated with a low glomerular filtration rate, high proteinuria, and high-grade histopathological changes, including tubular atrophy, interstitial inflammation, and glomerular sclerosis. In a mouse UUO model, renal protein expression of COL1 and phosphorylated p38 were significantly increased, and the protein expression of COL1 and phosphorylated p38 decreased in mice administered 10 mg/kg/day p38 MAPK inhibitor. We found that kidney interstitial fibrosis is associated with increased immunoactivity of phosphorylated p38 in a UUO mouse model and in human IgA nephropathy patients and that the anti-fibrotic effect of p38 MAPK inhibition can be confirmed using immunohistochemical staining for phosphorylated p38 in kidney tissue.

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Section: Discussionmentioning

confidence: 99%

p38 MAPK activity is associated with the histological degree of interstitial fibrosis in IgA nephropathy patients

Lee

Hwang

et al. 2019

PLoS ONE

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“…The profibrotic process in each organ involves unopposed collagen accumulation [ 11 , 45 ]. In addition to this collagen accumulation, most fibrotic lesions in systemic fibrotic diseases are associated with the upregulated expression of POSTN, which is mainly produced from activated fibroblasts [ 4 , 6 , 7 , 21 , 35 , 46 – 49 ]. Notably, accumulated evidence indicates that stromal POSTN plays a key role in augmenting the production of collagen [ 48 , 50 ] and suggests that POSTN is a potential target for the treatment of systemic fibrosis [ 4 , 6 , 7 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

NRF2 Activation Inhibits Both TGF‐β1‐ and IL‐13‐Mediated Periostin Expression in Fibroblasts: Benefit of Cinnamaldehyde for Antifibrotic Treatment

Mitamura

Murai

Mitoma

et al. 2018

Oxidative Medicine and Cellular Longevity

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Systemic fibrosing or sclerotic disorders are life-threatening, but only very limited treatment modalities are available for them. In recent years, periostin (POSTN), a major extracellular matrix component, was established by several studies as a novel key player in the progression of systemic fibrotic disease. In this research, we revealed the involvement of oxidative stress in the expression of POSTN induced by TGF-β1 and IL-13 in dermal fibroblasts. We found that the antioxidant cinnamaldehyde activated the NRF2/HMOX1 pathway. Cinnamaldehyde also alleviated TGF-β1- and IL-13-mediated production of reactive oxygen species and subsequent POSTN upregulation in dermal fibroblasts. In contrast, NRF2 silencing abolished the cinnamaldehyde-mediated downregulation of POSTN. These results suggest that cinnamaldehyde is a broad inhibitor of POSTN expression covering both TGF-β1 and IL-13 signaling. Cinnamaldehyde may thus be beneficial for the treatment of systemic fibrotic diseases.

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“…TGF-β1 signaling also anticipates irradiation-induced multiple organ fibrosis, such as kidney, lung and intestine. Inhibition of TGF-β1 signaling ameliorates irradiation-induced organ fibrosis by decreasing expression of collagen I and II [ 35 , 36 ]. Recent data indicate that NF-κB signaling is activated in acute renal injuries post irradiation, which is related to irradiation-induced inflammation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mTORC1 signaling protects kidney from irradiation-induced toxicity via accelerating recovery of renal stem-like cells

Shao

Yang

et al. 2018

Stem Cell Res Ther

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BackgroundIrradiation-induced kidney damage is inevitable during radiotherapeutic practice, which limits effective radiotherapy doses on tumor treatment. In the present study, the role of mTOR complex 1 (mTORC1) signaling was investigated in irradiation-induced renal injuries.MethodsMice were exposed to 8.0-Gy X-ray of total body irradiation and subsequently treated with rapamycin. Changes of renal morphology were assessed by hematoxylin and eosin staining. Expression of pS6 and CD133 was detected via immunostaining. Cellular apoptosis and proliferation were measured by TUNEL, caspase-3 and BrdU staining. Activation of mTORC1, TGF-β and NF-κB signaling pathways was determined through western blot analysis.ResultsOur data displayed that irradiation disrupted the structures of renal corpuscles and tubules and decreased the density of CD133+ renal stem-like cells, which were related with increasing cellular apoptosis and decreasing cell proliferation post exposure. Activation of mTORC1, TGF-β and NF-κB signaling pathways was determined in irradiated renal tissues, which were inhibited by rapamycin treatment. Application of rapamycin after irradiation decreased cellular apoptosis and increased autophagy and cell proliferation in renal tissues. The density of CD133+ renal stem-like cells was significantly increased in irradiated kidneys after rapamycin treatment. The morphology of irradiated renal corpuscles and tubules was gradually recovered upon rapamycin treatment.ConclusionsThese findings indicate that inhibition of mTORC1 signaling by rapamycin ameliorates irradiation-induced renal toxicity mediated by decreasing cellular apoptosis and increasing CD133+ renal stem-like cells.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0963-5) contains supplementary material, which is available to authorized users.

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Experimental Inhibition of Periostin Attenuates Kidney Fibrosis

Cited by 26 publications

References 42 publications

p38 MAPK activity is associated with the histological degree of interstitial fibrosis in IgA nephropathy patients

p38 MAPK activity is associated with the histological degree of interstitial fibrosis in IgA nephropathy patients

NRF2 Activation Inhibits Both TGF‐β1‐ and IL‐13‐Mediated Periostin Expression in Fibroblasts: Benefit of Cinnamaldehyde for Antifibrotic Treatment

Inhibition of mTORC1 signaling protects kidney from irradiation-induced toxicity via accelerating recovery of renal stem-like cells

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