Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis

Jinde, Kiichiro; Nikolic-Paterson, David J.; Huang, Xiao Ru; Sakai, Hideto; Kurokawa, Kiyoshi; Atkins, Robert C.; Lan, Hui‐Yao

doi:10.1053/ajkd.2001.27693

Cited by 128 publications

(99 citation statements)

References 24 publications

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“…a FSP1/S100A4-positive interstitial cells, accumulated around diseased distal tubules (asterisks), display CD45 in their plasma membrane; in a few CD45-positive cells FSP1/S100A4 was not detected. b Mononuclear cells within a capillary lumen; the two FSP1/S100A4-labeled cells are labeled by CD45 as well; bars a 50 lm, b 10 lm suggest that transformation of epithelial cells into fibroblasts/myofibroblasts contributes decisively to fibrosis in various renal diseases (Iwano and Neilson 2004;Iwano et al 2002;Jinde et al 2001;Kalluri and Neilson 2003;Liu 2004;Ng et al 1998;Okada et al 2000;Strutz and Neilson 2003;Yang and Liu 2002). …”

Section: Discussionmentioning

confidence: 99%

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

Hir

Hegyi

Cueni-Loffing

et al. 2005

Histochem Cell Biol

117

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Fibrosis is considered as a central factor in the loss of renal function in chronic kidney diseases. The origin of fibroblasts and myofibroblasts that accumulate in the interstitium of the diseased kidney is still a matter of debate. It has been shown that accumulation of myofibroblasts in inflamed and fibrotic kidneys is associated with upregulation of fibroblast-specific protein 1 (FSP1, S100A4), not only in the renal interstitium but also in the injured renal epithelia. The tubular expression of FSP1 has been taken as evidence of myofibroblast formation by epithelial-mesenchymal transition (EMT). The identity of FSP1/S100A4 cells has not been defined in detail. We originally intended to use FSP1/ S100A4 as a marker of putative EMT in a model of distal tubular injury. However, since the immunoreactivity of FSP1 did not seem to fit with the distribution and shape of fibroblasts or myofibroblasts, we undertook the characterization of FSP1/S100A4-expressing cells in the interstitium of rodent kidneys. We performed immunolabeling for FSP1/S100A4 on thin cryostat sections of perfusion-fixed rat and mouse kidneys with peritubular inflammation, induced by thiazides and glomerulonephritis, respectively, in combination with ecto-5¢-nucleotidase (5¢NT), recognizing local cortical peritubular fibroblasts, with CD45, MHC class II, CD3, CD4 and Thy 1, recognizing mononuclear cells, with alpha smooth muscle actin (aSMA), as marker for myofibroblasts, and vimentin for intracellular intermediate filaments in cells of mesenchymal origin. In the healthy interstitium of rodents the rare FSP1/S100A4+ cells consistently co-expressed CD45 or lymphocyte surface molecules. Around the injured distal tubules of rats treated for 3-4 days with thiazides, FSP1+/ S100A4+, 5¢NT+, aSMA+, CD45+ and MHC class II+ cells accumulated. FSP1+/S100A4+ cells consistently co-expressed CD45. In the inflamed regions, aSMA was co-expressed by 5¢NT+ cells. In glomerulonephritic mice, FSP1+/S100A4+ cells co-expressed Thy 1, CD4 or CD3. Thus, in the inflamed interstitium around distal tubules of rats and of glomerulonephritic mice, the majority of FSP1+ cells express markers of mononuclear cells. Consequently, the usefulness of FSP1/S100A4 as a tool for detection of (myo)fibroblasts in inflamed kidneys and of EMT in vivo is put into question. In the given rat model the consistent coexpression of aSMA and 5¢NT suggests that myofibroblasts originate from resident peritubular fibroblasts.

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Section: Discussionmentioning

confidence: 99%

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

Hir

Hegyi

Cueni-Loffing

et al. 2005

Histochem Cell Biol

117

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“…Taken together, to identify the EMT, α-SMA and vimentin expressions are available, but desmin can not be used as a marker of EMT 45 . α-SMA-and vimentinexpressing renal epithelia have been also observed in biopsy specimens from human diseased kidneys 3,66 , but these studies have not investigated desmin expression. Because metanephrogenic blastemal cells are a stem cell population that has the capacity to differentiate either into epithelium (except collecting ducts) or interstitium 67-69 , it is likely that renal EMT is a reverse event of nephrogenesis.…”

Section: Immunophenotypical Changes Of Kidney-related Cell Lines By Tmentioning

confidence: 99%

“…Renal interstitial fibrosis, an intractable disease, is regarded as the common final pathway in renal diseases regardless of the etiology [1][2][3] . The renal fibrosis has greater im pact on the progression of ren al disease t han glomerulosclerosis 3,4 .…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

Yamate

2007

J Toxicol Pathol

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Macrophages and myofibroblasts play important roles in progressive renal fibrosis. Using cisplatin-induced rat renal fibrosis models, the author has investigated patho-biological characteristics of these cells. Macrophages seen in the fibrotic areas involve exudate macrophages, resident macrophages and antigen-presenting cells (activated dendritic cells and macrophages). In the early stages of renal fibrosis, exudate and resident macrophages are key cells for induction of myofibroblasts via producing fibrogenic factors such as transforming growth factor (TGF)-β1 and plateletderived growth factor (PDGF)-BB. In addition, these macrophages have capacity to phagocytize apoptotic bodies for clearance. [185][186][187][188][189][190][191][192][193][194][195]

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“…TGF-β1 is a key mediator responsible for transdifferentiation in vivo and in vitro (7,46,48,49). It has previously been shown that TGF-β1 has an important role in altering the phenotype of renal epithelial cells, and that this significantly contributes to the profibrotic effects (50).…”

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confidence: 99%

Allicin inhibits tubular epithelial-myofibroblast transdifferentiation under high glucose conditions in vitro

Huang

Zheng

Dong

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Previous studies have suggested that tubular epithelial-mesenchymal transition (EMT) is an important event in renal tubulointerstitial fibrosis, which is a clinical characteristic of diabetic nephropathy. The present study aimed to investigate the effect of allicin, the major biological active component of garlic, on the EMT of a human renal proximal tubular epithelial cell line (HK-2) cultured under high glucose concentrations. HK-2 cells were exposed for 48 h to 5.5 or 25 mmol/l D-glucose, 25 mmol/l D-glucose plus allicin (2.5, 5, 10 or 20 µg/ml) or 25 mmol/l D-glucose plus 20 µmol/l PD98059, a selective inhibitor of the mitogen activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathway. The EMT of HK-2 cells was assessed by analyzing the protein expression of E-cadherin, α-smooth muscle actin (α-SMA), vimentin and collagen I via immunocytochemistry. In addition, reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression levels of transforming growth factor (TGF)-β1 and phosphorylated (p)-ERK1/2. Marked morphological changes were observed in HK-2 cells cultured under high glucose conditions, and these changes were abrogated by simultaneous incubation with allicin and PD98059. The expression levels of α-SMA, vimentin and collagen I were significantly increased in HK-2 cells cultured under high glucose conditions, as compared with those cultured under normal glucose conditions (P<0.01). Conversely, the expression levels of E-cadherin were significantly decreased upon stimulation with high glucose (P<0.01). Furthermore, the expression levels of TGF-β1 and p-ERK1/2 were significantly upregulated in HK-2 cells cultured under high glucose conditions, as compared with those cultured under normal glucose conditions (P<0.05).Allicin partially reversed the high-glucose-induced increase in α-SMA, vimentin and collagen I expression (P<0.01 at 20 µg/ml), increased the expression of E-cadherin, and significantly downregulated the high glucose-induced expression of TGF-β1 and p-ERK1/2 in a dose-dependent manner (P<0.05). The results of the present study suggested that high glucose concentrations induced the EMT of HK-2 cells, and that allicin was able to inhibit the EMT, potentially via regulation of the ERK1/2-TGF-β1 signaling pathway. IntroductionTubulointerstitial fibrosis, which is considered the final common pathway of progressive kidney diseases and eventually leads to end-stage renal disease, is a result of the tubular epithelial-to-mesenchymal transition (EMT) and excessive accumulation of extracellular matrix (ECM) that characterize the majority of chronic kidney diseases, including diabetic nephropathy (DN) (1). Previous studies have demonstrated that high glucose conditions induce the EMT in renal proximal tubular cells in vitro and in vivo (2-5). In addition, it has been reported that myofibroblast formation is a critical step in the pathogenesis of tubulointerstitial fibrosis, and it has been shown to be a key step in...

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Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis

Cited by 128 publications

References 24 publications

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys

Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

Allicin inhibits tubular epithelial-myofibroblast transdifferentiation under high glucose conditions in vitro

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