Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation

Inagi, Reiko; Nangaku, Masaomi; Onogi, Hiroshi; Ueyama, Hiroshi; Kitao, Yasuko; Nakazato, Kiyokazu; Ogawa, Satoshi; Kurokawa, Kiyoshi; Couser, William G.; Miyata, Toshio

doi:10.1111/j.1523-1755.2005.00736.x

Cited by 103 publications

(87 citation statements)

References 48 publications

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“…Previous reports by our and other groups have emphasized a pathogenic role of ER stress in glomerular and tubular epithelial injury. 14,17,20,21 Immunohistochemical analysis in this study showed upregulation of the ER chaperones GRP78 and ORP150 in the glomeruli of rats with antiThy1 nephritis. Furthermore, activation of the PERK pathway, a UPR pathway involved in the downregulation of translation, was also detected in the glomeruli of these rats.…”

Section: Discussionmentioning

confidence: 99%

“…Isolated glomeruli were obtained from the experimental rats using a conventional sieving method 17 and homogenized in a sample buffer (0.35 M Tris-HCl [pH 6.8], 10% SDS, 36% glycerol, 5% ␤-mercaptoethanol, and 0.012% bromophenol blue). The obtained test samples (50 g of proteins for each) were electrophoresed on SDS-PAGE and transferred to a polyvinylidene fluoride membrane (Amersham Biosciences, Piscataway, NJ).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…8,9 ER stress is associated with a range of diseases, including ischemia/reperfusion injury, neuronal degeneration, and diabetes. 3,5,10 -12 Accumulating evidence, including our previous studies, suggests a pathophysiologic role of ER stress in the kidney, [13][14][15][16][17][18][19] the details of which remain unclear. Here, we investigated whether therapeutic approaches targeting ER stress might be effective against renal disease using a model of mesangioproliferative glomerulonephritis in rats.…”

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confidence: 99%

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Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

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106

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Accumulating evidence suggests a pathophysiologic role of endoplasmic reticulum (ER) stress in kidney disease. This study investigated the potential of therapeutic approaches targeting ER stress in the anti-Thy1 model of mesangioproliferative glomerulonephritis in rats. Immunohistochemistry and Western blotting showed a time-dependent increase in the expression of the ER stress-inducible chaperones glucose-regulated protein 78 (GRP78) and oxygen-related protein 150 in isolated glomeruli, especially in the glomerular epithelial cells and mesangial cells, after induction of anti-Thy1 nephritis. For evaluation of whether preconditioning with ER stress ameliorates the severity of disease, rats were pretreated with a subnephritogenic dose of the ER stress inducer tunicamycin or thapsigargin for 4 d before disease was induced. Although preconditioning with ER stress had no effect on the degree of disease induction, it strongly ameliorated the manifestations of disease, evidenced by marked reductions in microaneurysm formation, mesangial proliferation, and adhesion of Bowman's capsule to the glomerular tuft. This improvement in histologic damage was associated with reduced proteinuria (39.4 Ϯ 10.5 versus 126.1 Ϯ 18.1 mg/d; P Ͻ 0.01) and with attenuated increases in glucose-regulated protein 78 and oxygen-related protein 150 expression. Of note, pretreatment with tunicamycin or thapsigargin decreased the excessive ER stress-induced intracellular signaling observed in anti-Thy1 nephritis. In conclusion, preconditioning with ER stress ameliorates the severity of disease in rats with anti-Thy1 nephritis. These findings suggest the possibility of therapeutic approaches targeting ER stress in mesangioproliferative glomerulonephritis.

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Section: Discussionmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

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106

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“…Common insults such as the accumulation of advanced glycation end products (AGEs) and the activation of their receptors have been implicated in not only the pathogenesis of DN (Forbes et al 2003, Wendt et al 2003, Tan et al 2010 but also the induction of ER stress (Inagi et al 2005, Cheng et al 2006. Moreover, the accumulation of AGEs within the skin (representing tissue accumulation) also predicts those T1D individuals at a greatest risk of developing nephropathy (Yu et al 2006).…”

Section: Mechanisms Culminating In a Stressed Diabetic Podocyte Ermentioning

confidence: 99%

“…Indeed, ER stress is induced in podocytes when acutely stimulated under both highglucose (Cao et al 2014) and low-glucose (Fujii et al 2006) conditions, and it is apparent that there are regulatory mechanisms to alleviate this stress when podocytes are chronically exposed to hyperglycaemic conditions (Inagi et al 2005). Given that cell survival is promoted through the activation of autophagy in the advent of ER stress induced in mammalian cells in a high-glucose environment (Ogata et al 2006), it is likely that compensatory modifications to the ER could be directly linked to autophagy.…”

Section: Mechanisms Culminating In a Stressed Diabetic Podocyte Ermentioning

confidence: 99%

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Zhuang¹,

Forbes²

2014

Journal of Endocrinology

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The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts. Key Words" endoplasmic reticulum stress " diabetic nephropathy

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Cannabinoid receptor 1 mediates palmitic acid‐induced apoptosis via endoplasmic reticulum stress in human renal proximal tubular cells

Lim

Han

et al. 2010

Journal Cellular Physiology

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The endocannabinoid system (ECS) is activated at the onset of obesity and diverse metabolic diseases. Endocannabinoids mediate their physiological and behavioral effects by activating specific cannabinoid receptors, mainly cannabinoid receptor 1 (CB(1)R). Diabetic nephropathy (DN) is induced by hyperlipidemia, and renal proximal tubule cells are an important site for the onset of DN. However, the pathophysiology of CB(1)R, especially in the hyperlipidemia of DN, has not been elucidated. Therefore, we examined the effect of palmitic acid (PA) on CB(1)R expression and its related signal pathways in human renal proximal tubular cells (HK-2 cells). PA significantly increased CB(1)R mRNA and protein levels and induced CB(1)R internalization. PA-induced activation of CB(1)R is prevented by the treatment of AACOCF(3) (a cPLA(2) inhibitor), indomethacin and NS398 (a COX 2 inhibitors). Indeed, PA increased cPLA(2), and COX-2 but not COX-1. We also investigated whether the PA-induced activation of CB(1)R is linked to apoptosis. As a result, AM251 (a CB(1)R antagonist) attenuated PA-mediated apoptosis in a concentration-dependent manner. Furthermore, PA decreased GRP78 expression and induced increases in the endoplasmic reticulum (ER) stress signaling pathways p-PERK, p-eIF2α, p-ATF4, and CHOP, which were blocked by AM251 treatment. Moreover, PA increased the Bax/Bcl-2 ratio, cleaved PARP, and caspase-3 levels. The PA-induced apoptotic effects were decreased with CB(1)R-specific antagonist (AM251) treatment and CB1 si-RNA transfection. In conclusion, PA induced apoptosis through ER stress via CB(1)R expression in human proximal tubule cells. Our results provide evidence that CB(1)R blockade may be a potential anti-diabetic therapy for the treatment of DN.

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Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation

Abstract: This paper implicates a crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury.

Cited by 103 publications

References 48 publications

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Cannabinoid receptor 1 mediates palmitic acid‐induced apoptosis via endoplasmic reticulum stress in human renal proximal tubular cells

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