Involvement of Endoplasmic Reticulum Stress in Albuminuria Induced Inflammasome Activation in Renal Proximal Tubular Cells

Li, Fang; Xie, Da; Wu, Xian; Cao, Hongdi; Su, Wei‐Fang; Yang, Junwei

doi:10.1371/journal.pone.0072344

Cited by 94 publications

(78 citation statements)

References 31 publications

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“…21 In vitro cell studies also support changes taking place in PTC with protein overload. [26][27][28] Finally, a study in Wistar rats using three albumin injections, versus two as in our study, showed no change in the glomerular size selectivity. 29 For the present study, we chose an acute albumin overload model using two albumin injections in normal healthy animals.…”

Section: Discussionsupporting

confidence: 46%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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Evidence from multiple studies supports the concept that both glomerular filtration and proximal tubule (PT) reclamation affect urinary albumin excretion rate. To better understand these roles of glomerular filtration and PT uptake, we investigated these processes in two distinct animal models. In a rat model of acute exogenous albumin overload, we quantified glomerular sieving coefficients (GSC) and PT uptake of Texas Red-labeled rat serum albumin using two-photon intravital microscopy. No change in GSC was observed, but a significant decrease in PT albumin uptake was quantified. In a second model, loss of endogenous albumin was induced in rats by podocyte-specific transgenic expression of diphtheria toxin receptor. In these albumin-deficient rats, exposure to diphtheria toxin induced an increase in albumin GSC and albumin filtration, resulting in increased exposure of the PTs to endogenous albumin. In this case, PT albumin reabsorption was markedly increased. Analysis of known albumin receptors and assessment of cortical protein expression in the albumin overload model, conducted to identify potential proteins and pathways affected by acute protein overload, revealed changes in the expression levels of calreticulin, disabled homolog 2, NRF2, angiopoietin-2, and proteins involved in ATP synthesis. Taken together, these results suggest that a regulated PT cell albumin uptake system can respond rapidly to different physiologic conditions to minimize alterations in serum albumin level. 27: 482-494, 201627: 482-494, . doi: 10.1681 While the clinical relevance of proteinuria, and especially albuminuria, has been well documented, the quantitative and mechanistic significance of different components to albumin excretion remains an area of considerable excitement and debate. 1 Recent data from several laboratories utilizing different approaches have delineated a role of proximal tubules (PTs) in regulation of albumin reabsorption and reclamation. 2 Furthermore, albumin transcytosis has been visualized in PT cells 3 and FcRn has been shown to mediate the transcytosis of albumin across PTCs, 4 as it is known to do for many other cell types. 2 Therefore, the present studies were conducted to begin differentiating and quantifying glomerular and PT contributions to albuminuria under physiologic and disease conditions. This understanding is important because before appropriate therapies can be developed to modulate albuminuria, the structural, functional and mechanistic characterization need to be better understood and interrelated. J Am Soc Nephrol

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Section: Discussionsupporting

confidence: 46%

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Wagner

Campos-Bilderback

Chowdhury

et al. 2016

Journal of the American Society of Nephrology

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“…22) However, the effect of UDCA on diabetic nephropathy has remained largely unknown. In the present study, we provide the verification for the protective actions of UDCA on diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic Acid Ameliorated Diabetic Nephropathy by Attenuating Hyperglycemia-Mediated Oxidative Stress

Wang

Chen

et al. 2016

Biological & Pharmaceutical Bulletin

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Oxidative stress has a great role in diabetes and diabetes induced organ damage. Endoplasmic reticulum (ER) stress is involved in the onset of diabetic nephropathy. We hypothesize that ER stress inhibition could protect against kidney injury through anti-oxidative effects. To test whether block ER stress could attenuate oxidative stress and improve diabetic nephropathy in vivo and in vitro, the effect of ursodeoxycholic acid (UDCA), an ER stress inhibitor, on spontaneous diabetic nephropathy db/db mice, ER stress inducer or high glucose-triggered podocytes were studied. Mice were assigned to 3 groups (n 6 per group): control group (treated with vehicle), db/db group (treated with vehicle), and UDCA group (db/db mice treated with 40 mg/ kg/d UDCA). After 8 weeks treatment, mice were sacrificed. Blood and kidneys were collected for the assessment of albumin/creatinine ratio, blood urea nitrogen (BUN), serum creatinine (SCr), insulin, total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), oxidized LDL-C, high density lipoprotein cholesterol (HDL-C), non-esterified fatty acid (NEFA), superoxide dismutase (SOD), catalase (CAT), methane dicarboxylic aldehyde (MDA), the expressions of SOD isoforms and glutathione peroxidase 1, as well as histopathological examination. In addition, generation of reactive oxygen species (ROS) was detected by 2′7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence. The results showed that UDCA alleviated renal ER stress-evoked cell death, oxidative stress, renal dysfunction, ROS production, upregulated the expression of Bcl-2 and suppressed Bax in vivo and in vitro. Hence, inhibition ER stress diminishes oxidative stress and exerts renoprotective effects.Key words diabetic nephropathy; podocyte; oxidative stress; reactive oxygen species Diabetic mellitus is a global health problem in which blood glucose is persistently elevated and generates a cascade of events in organ including kidney.1,2) The population with diabetes has been increasing worldwide and diabetic nephropathy (DN) now is a leading cause of end-stage renal failure.3)The mechanisms by which hyperglycemia contributes to kidney remain limited due to various factors modulate the plasma glucose in the body. The management of DN is based on the control of plasma glucose levels. 4) Reviewing number of studies demonstrates that reactive oxygen species (ROS), associated with increased plasma glucose, has been implicated in the pathogenesis of DN, which results in the over-production of extracellular matrix proteins, mitochondrial damage and glomeruli injury.5-8) Therefore, oxidative stress attenuation is an important pathway in DN prevention. 9)The endoplasmic reticulum (ER) regulates the folding of secretory and intracellular calcium.10) Excessive unfolded proteins in the lumen of ER produces stress and contributed to the disorder of intracellular signal transduction pathways. 11)A number of pathophysiological conditions are associated with ER stress included diabetes. ER stress is a key mediator of β...

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“…The increased UPR in diabetes reveals the existence of ERS (33), including upregulation of nuclear transcription factors such as PERK. Fang et al reported that ERS appeared to play an important part in albuminuriaprovoked inflammasome activation and elimination of ERS via tauroursodeoxycholic acid (TUDCA), which might represent a novel avenue for attenuating kidney epithelial cell damage caused by albuminuria (34). The UPR is a homeostatic response that allows the cells to cope with stressful conditions associated with increased misfolded or unfolded protein loads; failure of this mechanism is referred to as the ERS response (9).The ERS response has been found to play a key role in a growing number of pathological conditions such as DN (10,34,35), and the ERS response is considered to be a cause of chronic inflammation (36).…”

Section: Discussionmentioning

confidence: 99%

TGP attenuates endoplasmic reticulum stress and regulates the expression of thioredoxin-interacting protein in the kidneys of diabetic rats

Shao

et al. 2016

BST

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Involvement of Endoplasmic Reticulum Stress in Albuminuria Induced Inflammasome Activation in Renal Proximal Tubular Cells

Cited by 94 publications

References 31 publications

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

Ursodeoxycholic Acid Ameliorated Diabetic Nephropathy by Attenuating Hyperglycemia-Mediated Oxidative Stress

TGP attenuates endoplasmic reticulum stress and regulates the expression of thioredoxin-interacting protein in the kidneys of diabetic rats

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