Albumin-Induced Epithelial Mesenchymal Transformation

Ibrini, J; Fadel, Shaema S.; Chana, Ravinder S.; Brunskill, Nigel; Wagner, Barbara; Johnson, Tim; Nahas, A. M. El

doi:10.1159/000336822

Cited by 16 publications

(15 citation statements)

References 52 publications

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“…We showed, in an isolated system, free of hemodynamic influences, that albumin induces changes compatible with EMT, which is the most accepted pathophysiological mechanism to explain renal fibrosis in progressive renal disease. This important fact has been recently demonstrated in normal rat tubular cells NRK52E (27), and here we added that EMT may be prevented by bradykinin, an effect that is reversed by icatibant.…”

Section: Discussionsupporting

confidence: 62%

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Ardiles

Cárdenas

Burgos

et al. 2013

American Journal of Physiology-Renal Physiology

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The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

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Section: Discussionsupporting

confidence: 62%

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Ardiles

Cárdenas

Burgos

et al. 2013

American Journal of Physiology-Renal Physiology

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“…As expected, cellular treatment with albumin for 72 hr markedly increased the levels of α‐SMA, indicating the involvement of EMT in albumin‐induced renal injury. These findings are consistent with previous studies, which revealed a clear induction of EMT in rat renal tubular cells following exposure to albumin (Hu et al, ; Ibrini et al, ). A previous study showed that metformin treatment significantly suppresses albumin‐induced EMT in human proximal tubular cells (Lee et al, ).…”

Section: Discussionsupporting

confidence: 94%

“…Intriguingly, a direct association between albuminuria and EMT was reported. Studies in rat renal tubular cells revealed a clear induction of EMT − marked by a decrease in the levels of epithelial marker E‐cadherin and an increase in the expression of mesenchymal markers − α‐smooth muscle actin, fibroblast‐specific protein 1, and collagen I − following exposure to albumin (Hu et al, ; Ibrini et al, ).…”

Section: Introductionmentioning

confidence: 99%

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

Allouch

Munusamy

2017

Journal Cellular Physiology

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Proteinuria (albuminuria) plays a crucial role in the etiology of chronic kidney disease (CKD) via alteration of multiple signaling pathways and cellular process in renal cells. The objectives of this study are to investigate the effects of activation of the energy-sensing molecule AMP-activated kinase (AMPK) in renal cells using metformin on endoplasmic reticulum (ER) stress, AKT, mTOR, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis that are thought to mediate renal cell injury during proteinuria, and to dissect the AMPK- and non-AMPK mediated effects of metformin using an in vitro model of albumin-induced renal cell injury. Rat renal proximal tubular (NRK-52E) cells were exposed to 10 and 15 mg/ml of albumin for 72 h in the presence of 1 mM Metformin and/or 0.5 µM compound C, and assessed for alterations in the aforementioned pathways. Metformin treatment restored AMPK phosphorylation and augmented autophagy in renal cells exposed to albumin. In addition, metformin treatment attenuated the albumin-induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin-mediated inductions of EMT marker (α-SMA), pro-apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells. Blockade of metformin-induced AMPK activation with compound C blunted the ER defense response and autophagy but had no effect on the markers of EMT and apoptosis in our model. Our studies suggest that metformin protects renal cells against proteinuric cytotoxicity via suppression of AKT and mTOR activation, inhibition of EMT and apoptosis, and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms, respectively.

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“…Emerging evidence demonstrates that EMT is key in renal tubulointerstitial fibrosis (1,3). In the present study, a prolonged albumin overload model was used to mimic the effects of chronic proteinuria to induce EMT, the results demonstrated that there was a significant decrease in the viability of HKC cells exposed to HSA, and HSA treatment reduced the expression levels of the epithelial marker CK and increased the expression levels of the mesenchymal marker vimentin, suggesting that HSA induced EMT in HKC cells, which is consistent with the results of previous studies (16,17).…”

Section: Discussionsupporting

confidence: 90%

HOXA13 exerts a beneficial effect in albumin-induced epithelial-mesenchymal transition via the glucocorticoid receptor signaling pathway in human renal tubular epithelial cells

et al. 2016

Molecular Medicine Reports

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Previous studies have suggested that albumin-induced renal tubular epithelial cell injury contributes to renal interstitial fibrosis. Epithelial-mesenchymal transition (EMT) is known to be a key mechanism in the pathogenesis and progression of renal interstitial fibrosis. Homeobox protein HOX‑A13 (HOXA13) is a nuclear transcriptional factor that has been reported to be involved in renal fibrosis. However, the mechanism underlying the effect of HOXA13 in human serum albumin (HSA)‑induced EMT in HKC renal tubular epithelial cells remains to be elucidated. Thus, the aim of the present study was to investigate the role of HOXA13 in HSA‑induced EMT in HKC cells and the potential mechanism of the glucocorticoid receptor (GR) signaling pathway. The protein and mRNA expression levels of HOXA13, cytokeratin, and vimentin were determined by western blot analysis and reverse transcription‑quantitative polymerase chain reaction in HKC cells, which were co‑incubated with HSA at different concentrations or for different time periods. The results demonstrated that HOXA13 mRNA and protein expression decreased in a dose‑ and time‑dependent manner when induced by HSA in HCK cells. The liposomal transfection experiment suggested that overexpression of HOXA13 activated the GR signal, which inhibits HSA-induced EMT. HOXA13 is involved in HSA‑induced EMT in HKC cells and upregulation of HOXA13 exerts a beneficial effect in EMT, which may be associated with the GR signaling pathway.

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Albumin-Induced Epithelial Mesenchymal Transformation

Cited by 16 publications

References 52 publications

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

HOXA13 exerts a beneficial effect in albumin-induced epithelial-mesenchymal transition via the glucocorticoid receptor signaling pathway in human renal tubular epithelial cells

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