Gender differences control the susceptibility to ER stress-induced acute kidney injury

Hodeify, Rawad; Megyesi, Judit; Tarcsafalvi, Adel; Mustafa, Hossam; Seng, Nang San Hti Lar; Price, Peter M.

doi:10.1152/ajprenal.00590.2012

Cited by 72 publications

(60 citation statements)

References 35 publications

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“…A mouse model of TM-induced ER stress was induced by a single intraperitoneal injection of TM (2 mg/kg). In this model, it has been reported that male mice show high induction of ER stress markers such as GRP78 and CHOP with proximal tubular damages in outer cortex [27]. Mice were randomly divided into 3 groups: control mice (n = 5), mice with TM injection (n = 5), mice with TM injection plus SRT1720 (n = 5).…”

Section: Methodsmentioning

confidence: 99%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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Background: Endoplasmic reticulum (ER) stress is emerging as an important factor in the development of organ fibrosis. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. SIRT1, a class III histone deacetylase, has been found to exert beneficial effects in kidney diseases. However, it is largely unknown whether and how SIRT1 suppresses the ER stress. We postulated that upregulation of SIRT1 would suppress the ER stress through induction of heme oxygenase-1 (HO-1) and thioredoxin. Methods: HK-2 tubular cells, experimental mouse models of tunicamycin (TM)-induced ER stress and unilateral ureteral obstruction (UUO) were used. Expression of ER stress-induced protein was measured by Western blot analysis and immunohistochemical staining. ER stress was induced by chemical ER stress inducers [TM [,]thapsigargin (TG)] and non-chemical inducers such as angiotensin II, aldosterone, high glucose and albumin. Results: SIRT1 activator (SRT1720) induced SIRT1 expression in a time- and dose-dependent manner in HK-2 cells. SRT1720 suppressed the TM- or TG-induced ER stress, as shown by inhibition of TM- or TG-induced upregulation of glucose-related protein 78 (GRP78), phosphor-specific eukaryotic translation initiation factor-2α and C/EBP homologous protein through HO-1 and thioredoxin, which were abolished by pretreatment with SIRT1 inhibitor (sirtinol). SRT1720 also suppressed the ER stress induced by angiotensin II, aldosterone, high glucose and albumin. In animal studies, treatment with SRT1720 reduced the tubular expression of GRP78 and increased the expression of HO-1 and thioredoxin. SRT1720 also reduced the UUO-induced renal fibrosis. Conclusion: SIRT1 may serve as a promising therapeutic target by reducing ER stress and fibrosis.

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Section: Methodsmentioning

confidence: 99%

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Chang

Kim

Baek

et al. 2016

Nephron

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“…Moreover, given that the outer medulla expresses ET A receptors, these studies suggest that the ET A receptor is pro-apoptotic in this particular rodent model. Tunicamycin can induce endoplasmic reticulum (ER) stress-and mitochondrial-mediated apoptosis (18), although the direct involvement of ET-1 was not tested in this study. Using the ET B -deficient rat as an experimental model, our group previously reported that pharmacological blockade of the ET A receptor ameliorates tunicamycin-induced renal ER stress and apoptosis in transgenic control rats, while failing to do so in the ET B -deficient rats (8).…”

Section: Working Hypothesis: Endothelium-derived Et-1 Mediates Renal mentioning

confidence: 98%

Endothelium-derived ET-1 and the development of renal injury

Miguel

Pollock

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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De Miguel C, Pollock DM, Pollock JS. Endothelium-derived ET-1 and the development of renal injury. Am J Physiol Regul Integr Comp Physiol 309: R1071-R1073, 2015. First published May 20, 2015 doi:10.1152/ajpregu.00142.2015.-The role of the vasoactive peptide endothelin-1 (ET-1) in renal injury is not fully understood. In this review, we examine the genetic models available to understand the autocrine/paracrine mechanisms by which ET-1 leads to renal injury and propose the working hypothesis that endothelium-derived ET-1 induces renal injury by initiating renal tubular apoptosis in a paracrine manner.endothelin-1; apoptosis; renal injury ENDOTHELIN-1 (ET-1) is an endogenous 21 amino acid peptide that has powerful vasoactive properties. ET-1 is produced by many cell types including endothelial cells (40), cardiomyocytes (36), mesangial cells (31), and different segments of the nephron, especially collecting ducts (22). Increased activity of the ET-1 system has been described in several cardiovascular and renal diseases (25,28). ET-1 stimulates two G proteincoupled receptor subtypes, ET A and ET B receptors, with the same affinity for both receptors (7). Activation of each receptor subtype leads to different, and often opposite, physiological and pathophysiological results (3). Renal cortical and inner medullary tubules are rich in ET B receptors, whereas outer medullary tubules express both ET A and ET B receptors. Overactivation of the renal ET A pathway leads to hypertrophy, inflammation, and fibrosis. Actions of the ET B pathway promote clearance of ET-1 from circulation, stimulation of nitric oxide, and/or prostacyclin release, as well as increased sodium and water excretion (23). Several cell-type-specific endothelin pathway knockout mouse models and an ET B receptor-deficient rat model facilitate in-depth investigations into the activation of cellular source(s) and actions of ET-1. This review highlights the rationale for the use of genetic rodent models to elucidate the autocrine and/or paracrine mechanisms of ET-1-dependent development of renal apoptosis and injury. Based on the literature and our own preliminary findings, studying tunicamycin-induced renal apoptosis in two ET-1 genetic rodent models provides rationale for a working hypothesis that endothelium-derived ET-1 induces renal tubular apoptosis by a paracrine mechanism. ET-1 Pathway, Apoptosis, and Renal InjuryRenal injury is preceded by tubular apoptosis and loss of nephrons (26). Apoptotic cell death is characterized by a series of changes in cellular morphology, such as shrinkage of the cell membrane, condensation of nuclear chromatin, cellular fragmentation, and engulfment of the apoptotic bodies by neighboring cells (21). Different vasoactive peptides have been implicated in the regulation of cellular apoptosis; however, contradictory reports in the literature do not provide a clear role of ET-1 in apoptosis and renal injury. Some studies indicate that ET-1 attenuates apoptosis in vascular smooth muscle cells (39), endothelial cells (11), and...

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“…1 This provides short-term protection from acute stress by ( a ) inhibiting global protein translation through phosphorylation of eIF2α, ( b ) increasing ER protein folding capacity through upregulation of ER chaperones, and ( c ) increasing ER-associated degradation. Following acute ischemia and nephrotoxicity (16, 20–22), ER stress is induced in kidney epithelial cells both in vivo and in vitro. Overexpression of the ER chaperones BiP/GRP78 (23) and ORP150 (24) or the use of chemical chaperones, such as PBA or TUDCA (25), which enhances the adaptive UPR, dampens the ER stress response by improving protein folding capacity and facilitating the trafficking of unfolded or misfolded proteins, thereby protecting cells and tissues against injury (23–25).…”

Section: Pathophysiologymentioning

confidence: 99%

Acute Kidney Injury

2016

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Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).

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Gender differences control the susceptibility to ER stress-induced acute kidney injury

Cited by 72 publications

References 35 publications

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Up-Regulation of SIRT1 Reduces Endoplasmic Reticulum Stress and Renal Fibrosis

Endothelium-derived ET-1 and the development of renal injury

Acute Kidney Injury

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