Cystathionine Protects against Endoplasmic Reticulum Stress-induced Lipid Accumulation, Tissue Injury, and Apoptotic Cell Death

Maclean, Kenneth N.; Greiner, Lori S.; Evans, Jeffrey R.; Sood, Sudesh K.; Lhoták, Šárka; Markham, Neil E.; Stabler, Sally P.; Allen, Robert H.; Austin, Richard C.; Balasubramaniam, Vivek; Jiang, Hua

doi:10.1074/jbc.m112.355172

Cited by 54 publications

(56 citation statements)

References 44 publications

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“…Recent studies have suggested the imbalance between the folding of proteins and ER capacity as a cause of apoptosis (18,22), as an excessively prolonged UPR leads cell apoptosis (3,16). Stimulation by albumin overload may cause an accumulation of misfolded proteins in tubular cells and induce sustained ER stress.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy

Xiao

Fan

Wang

et al. 2016

American Journal of Physiology-Renal Physiology

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Our previous studies have suggested a critical role of reticulon (RTN)1A in mediating endoplasmic reticulum (ER) stress in kidney cells of animal models and humans with kidney diseases. A large body of evidence suggests that proteinuria itself can cause tubular cell injury leading to the progression of kidney disease. In the present study, we determined whether RTN1A mediates proteinuria-induced tubular cell injury through increased ER stress. We found that incubation of HK2 cells with human serum albumin induced the expression of RTN1A and ER stress markers, whereas knockdown of RTN1A expression attenuated human serum albumin-induced ER stress and tubular cell apoptosis in vitro. In vivo, we found that tubular cell-specific RTN1 knockdown resulted in a significant attenuation of tubular cell ER stress, apoptosis, and renal fibrosis in a model of albumin overload nephropathy. Based on these findings, we conclude that RTN1A is a key mediator for proteinuria-induced tubular cell toxicity and renal fibrosis.reticulon-1; kidney disease; proteinuria; renal tubular cells; endoplasmic reticulum stress; apoptosis PROTEINURIA has been postulated to contribute to tubular cell injury and interstitial fibrosis (2,19). Studies have shown that patients with higher levels of proteinuria are at a greater risk of progression to end-stage renal disease (20,24). However, the underlying mechanisms of albumin-induced tubulointerstitial injury are not completely understood. Currently, there is no specific and effective therapy available to reduce the progression of chronic kidney disease (CKD) induced by proteinuria.Endoplasmic reticulum (ER) stress has been shown to contribute to the development and progression of CKD (9, 10). Cells respond to ER stress by activating the unfolded protein response (UPR), and glucose-regulated protein of 78 kDa (GRP78) serves as a central regulator of three main UPR sensors, namely, activating transcription factor (ATF)6, inositol-requiring enzyme (IRE)-1␣, and protein kinase RNA-like ER kinase (PERK), that initiate the UPR signaling pathway under ER stress. Increased expression of these ER stress markers was observed in the tubulointerstitial compartment of human kidneys with proteinuric kidney diseases such as diabetic nephropathy and human immunodeficiency virus-associated nephropathy (7,12).In a recent study (7), we found that increased expression of reticulon (RTN)1 was associated with the progression of CKD and inversely correlated with kidney function (as assessed by the estimated glomerular filatration rate) in patients with diabetic nephropathy (DN). RTN1 belongs to a family of RTN proteins (RTN1-RTN4), which were first described in neuroendocrine cells to localize primarily to the ER membrane as ER-shaping proteins (8, 25). RTN4, also named Nogo, has previously been the only well-characterized member in the RTN family that has been shown to induce apoptosis, inhibit neuronal regeneration, and regulate protein trafficking (1,8,17). Our results showed that of the three RTN1 isoforms (RTN1A, RT...

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Section: Discussionmentioning

confidence: 99%

Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy

Xiao

Fan

Wang

et al. 2016

American Journal of Physiology-Renal Physiology

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“…In addition to the classic UPR gene Xbp1, we also found associations in genes with likely roles in ER stress (Dataset S5). CG7140 (human ortholog, H6PD) (28), Calx (NCX) (29), Mgstl (MGST1) (30), Cbs (CBS) (31), and KrT95D (PACS2) (32) are all genes that, when disrupted (in human disease or a model organism), induce or affect the ER stress response. For example, in the mouse, null mutations of H6PD, a gene encoding an ER resident protein, result in up-regulation of UPR associated genes in skeletal muscle (33).…”

Section: Snp In Xbp1mentioning

confidence: 99%

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Chow

Wolfner

Clark

2013

Proc. Natl. Acad. Sci. U.S.A.

111

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Natural genetic variation is a rich resource for identifying novel elements of cellular pathways such as endoplasmic reticulum (ER) stress. ER stress occurs when misfolded proteins accumulate in the ER and cells respond with the conserved unfolded protein response (UPR), which includes large-scale gene expression changes. Although ER stress can be a cause or a modifying factor of human disease, little is known of the amount of variation in the response to ER stress and the genes contributing to such variation. To study natural variation in ER stress response in a model system, we measured the survival time in response to tunicamycin-induced ER stress in flies from 114 lines from the sequenced Drosophila Genetic Reference Panel of wildderived inbred strains. These lines showed high heterogeneity in survival time under ER stress conditions. To identify the genes that may be driving this phenotypic variation, we profiled ER stressinduced gene expression and performed an association study. Microarray analysis identified variation in transcript levels of numerous known and previously unknown ER stress-responsive genes. Survival time was significantly associated with polymorphisms in candidate genes with known (i.e., Xbp1) and unknown roles in ER stress. Functional testing found that 17 of 25 tested candidate genes from the association study have putative roles in ER stress. In both approaches, one-third of ER stress genes had human orthologs that contribute to human disease. This study establishes Drosophila as a useful model for studying variation in ER stress and identifying ER stress genes that may contribute to human disease.

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“…Condensation of Hcy and serine can form cystathionine in a reaction catalyzed by cystathionine beta-synthase (MacLean et al, 2012), which is another major mechanism in the Hcy metabolic pathway. Hcy contains a free sulfhydryl group, and oxidizes with other thiols to form mixed disulfides, which results in the oxidization of other substances, including low-density lipoprotein (LDL).…”

Section: Introductionmentioning

confidence: 99%

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

Yang¹,

Tian²,

J³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Homocysteine (Hcy) is an independent risk factor of atherosclerosis through its involvement with the methionine cycle. In this study, we aimed to determine the blood vessel global methylation rate in Hcy-induced atherosclerosis in apolipoprotein-E-deficient (ApoE -/-) mice, and to explore the possible mechanism of this change in endothelial cells. ApoE -/-mice were divided into a hyperlipidemia (HLP) group, a hyperhomocysteinemia (HHcy) group, and an HHcy + folate + vitamin B12 (HHcy+FA+VB) group. Wild-type C57BL/6J mice were prepared as controls. Total Hcy, lipids, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) contents in serum were measured with an automatic biochemistry analyzer and high-performance liquid chromatography. Methylation of B1 repetitive elements in blood vessels was tested using nested methylation-specific-polymerase chain reaction (nMS-PCR). Endothelial cells (ECs) were pretreated with Hcy or by adding FA and VB. Lectin-like oxidized LDL receptor-1 (LOX-1) expressions were determined by quantitative PCR, Western blot, and nMS-PCR. The HHcy group displayed severe HLP and HHcy. SAM and SAH contents were also elevated in the HHcy group compared with other groups. Methylation of B1 repetitive elements was significantly increased in the HHcy group (0.5050 ± 0.0182) compared to the HLP (0.5158 ± 0.0163) and control (0.5589 ± 0.0236) groups. mRNA and protein expressions of LOX-1 increased (0.2877 ± 0.0341, 0.6090 ± 0.0547), whereas methylation expression decreased (0.5527 ± 0.0148) after 100 µM Hcy stimulation in ECs. In conclusion, Hcy-induced atherosclerosis was closely associated with induced hypomethylation status in the blood vessel, and this process was partially mediated by LOX-1 DNA methylation.

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Cystathionine Protects against Endoplasmic Reticulum Stress-induced Lipid Accumulation, Tissue Injury, and Apoptotic Cell Death

Cited by 54 publications

References 44 publications

Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy

Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

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