scholarly journals Salvianolic Acid B Protects Against Fatty Acid-Induced Renal Tubular Injury via Inhibition of Endoplasmic Reticulum Stress

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaoyi Mai ◽  
Xin Yin ◽  
Peipei Chen ◽  
Minzhou Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
High Fat Diet ◽  
Salvianolic Acid B ◽  
Tubular Injury ◽  
High Fat ◽  
Salvianolic Acid ◽  
Renal Tubular ◽  
Hk2 Cells

Background/Aims: Obesity-related kidney disease is associated with elevated levels of saturated free fatty acids (SFA). SFA lipotoxicity in tubular cells contributes to significant cellular apoptosis and injury. Salvianolic acid B (SalB) is the most abundant bioactive molecule from Radix Salviae Miltiorrhizae. In this study, we investigated the effect of SalB on SFA-induced renal tubular injury and endoplasmic reticulum (ER) stress, in vivo and in vitro.Methods: C57BL/6 mice were assigned to five groups: a control group with normal diet (Nor), high-fat diet group (HFD), and HFD with three different SalB treatment doses, low (SalBL; 3 mg/kg), medium (SalBM; 6.25 mg/kg), and high (SalBH; 12.5 mg/kg) doses. SalB was intraperitoneally injected daily for 4 weeks after 8 weeks of HFD. After 12 weeks, mice were sacrificed and kidneys and sera were collected. Apoptosis and ER stress were induced in human proximal tubule epitelial (HK2) cells by palmitic acid (PA, 0.6 mM), tunicamycin (TM, 1 μg/ml), or thapsigargin (TG, 200 nM) in vitro.Results: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks exhibited increased apoptosis (Bax and cleaved caspase-3) and ER stress (BIP, P-eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1s) markers expression in the kidney, compared with control mice, which were remarkably suppressed by SalB treatment. In vitro studies showed that PA (0.6 mM) induced apoptosis and ER stress in cultured HK2 cells. SalB treatment attenuated all the adverse effects of PA. However, SalB failed to inhibit TM or TG-induced ER stress in HK2 cells.Conclusion: The study indicated that SalB may play an important role in obesity-related kidney injury via mediating SFA-induced ER stress.

scholarly journals Protective Effects of Glucagon-Like Peptide-1 Analog on Renal Tubular Injury in Mice on High-Fat Diet

2017 ◽  
Vol 41 (3) ◽  
pp. 1113-1124 ◽  
Author(s):  
Honglei Guo ◽  
Hongmei Li ◽  
Bin Wang ◽  
Wei Ding ◽  
Lilu Ling ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
High Fat Diet ◽  
Tubular Injury ◽  
High Fat ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Renal Tubular

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD). Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 µg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting. Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (p<0.05). Increased AT1R induced by HFD and PA were blocked with GLP-1 treatment. In contrast, the level of angiotensin II after GLP-1 treatment was not significantly different between the HFD and HFDG mice. Conclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

scholarly journals Hepatocyte high-mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Minjie Lin ◽  
Jungke Long ◽  
Wenbo Li ◽  
Chenxuan Yang ◽  
Patricia Loughran ◽  
...  
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
High Mobility ◽  
High Mobility Group ◽  
High Fat ◽  
Rapid Weight Gain ◽  
Nonalcoholic Fatty Liver ◽  
Primary Mouse

Abstract Background Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Intracellular HMGB1 is critical for the biology of hepatocytes. However, the intracellular role of HMGB1 in hepatocellular steatosis is unknown. Therefore, we aimed to investigate the role of hepatocyte-specific HMGB1 (HC-HMGB1) in development of hepatic steatosis. Methods Wild type (WT) C57BL/6 and HC-HMGB1−/− mice were fed high-fat diet (HFD) or low-fat diet (LFD) for up to 16 weeks. Results As expected, HMGB1 translocated from nuclear into cytoplasm and released into circulation after HFD treatment. HC-HMGB1 deficiency significantly reduced circulating HMGB1, suggesting that hepatocyte is a major source of circulating HMGB1 during NAFLD. Unexpectedly, HC-HMGB1 deficiency promoted rapid weight gain with enhanced hepatic fat deposition compared with WT at as early as 4 weeks after HFD treatment. Furthermore, there was no difference between WT and HC-HMGB1−/− mice in glucose tolerance, energy expenditure, liver damage or systemic inflammation. Interestingly, hepatic gene expression related to free fatty acid (FFA) β-oxidation was significantly down-regulated in HC-HMGB1−/− mice compared with WT, and endoplasmic reticulum (ER) stress markers were significantly higher in livers of HC-HMGB1−/− mice. In vitro experiments using primary mouse hepatocytes showed absence of HMGB1 increased FFA-induced intracellular lipid accumulation, accompanied by increased ER-stress, significant downregulation of FFA β-oxidation, and reduced oxidative phosphorylation. Conclusions Our findings suggest that hepatocyte HMGB1 protects against dysregulated lipid metabolism via maintenance of β-oxidation and prevention of ER stress. This represents a novel mechanism for HMGB1-regulation of hepatocellular steatosis, and suggests that stabilizing HMGB1 in hepatocytes may be effective strategies for prevention and treatment of NAFLD.

High-fat diet leads to elevated lipid accumulation and endoplasmic reticulum stress in oocytes, causing poor embryo development

2020 ◽  
Vol 32 (14) ◽  
pp. 1169
Author(s):  
Arpitha Rao ◽  
Aparna Satheesh ◽  
Guruprasad Nayak ◽  
Pooja Suresh Poojary ◽  
Sandhya Kumari ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
High Fat ◽  
Developmental Potential ◽  
Diet Induced Obesity ◽  
Activating Transcription Factor ◽  
Elevated Lipid

The present study was designed to investigate the effect of diet-induced obesity on endoplasmic reticulum (ER) stress in oocytes. Swiss albino mice (3 weeks old) were fed with a high-fat diet (HFD) for 8 weeks. Oocytes were assessed for lipid droplet accumulation, oxidative stress, ER stress and their developmental potential invitro. High lipid accumulation (P&lt;0.01) and elevated intracellular levels of reactive oxygen species were observed in both germinal vesicle and MII oocytes of HFD-fed mice (P&lt;0.05 and P&lt;0.01 respectively compared with control). Further, expression of the ER stress markers X-box binding protein 1 (XBP1), glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and activating transcription factor 6 (ATF6) was significantly (P&lt;0.001) higher in oocytes of the HFD than control group. Oocytes from HFD-fed mice exhibited poor fertilisation and blastocyst rates, a decrease in total cell number and high levels of DNA damage (P&lt;0.01) compared with controls. In conclusion, diet-induced obesity resulted in elevated lipid levels and higher oxidative and ER stress in oocytes, which contributed to the compromised developmental potential of embryos.

scholarly journals AdipoRon Protects against Tubular Injury in Diabetic Nephropathy by Inhibiting Endoplasmic Reticulum Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shan Xiong ◽  
Yachun Han ◽  
Peng Gao ◽  
Hao Zhao ◽  
Na Jiang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Diabetic Nephropathy ◽  
Er Stress ◽  
High Glucose ◽  
Underlying Mechanism ◽  
Adiponectin Receptor ◽  
Tubular Injury ◽  
Beneficial Effects ◽  
Compound C

Endoplasmic reticulum (ER) stress has been reported to play a pivotal role in diabetic nephropathy (DN). AdipoRon is a newly developed adiponectin receptor agonist that provides beneficial effects for diabetic mice; however, its underlying mechanism remains to be delineated. Here, we demonstrated increased expression levels of ER stress markers, accompanied by upregulated levels of proinflammatory cytokines and increased expression of collagen I, fibronectin, Bax, and cleaved caspase 3 in the kidneys of db/db mice compared with control mice. Decreased expression of adiponectin receptor 1 (AdipoR1) and phosphorylated 5′AMP-activated kinase (p-AMPK) was also observed in the kidneys of db/db mice. However, these alterations were partially reversed by intragastric gavage with AdipoRon. In vitro, AdipoRon alleviated high-glucose-induced ER stress, oxidative stress, and apoptosis in HK-2 cells, a human tubular cell line. Moreover, AdipoRon restored the expression of AdipoR1 and p-AMPK in HK-2 cells exposed to high-glucose conditions. Additionally, these effects were partially abrogated by pretreatment with AdipoR1 siRNA, but this abrogation was ameliorated by cotreatment with AICAR, an AMPK activator. Furthermore, the effects of AdipoRon were also partially abolished by cotreatment with compound C. Together, these results suggest that AdipoRon exerts favorable effects on diabetes-induced tubular injury in DN by inhibiting ER stress mediated by the AdipoR1/p-AMPK pathway.

scholarly journals γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1242-1250 ◽  
Author(s):  
Chisayo Kozuka ◽  
Sumito Sunagawa ◽  
Rei Ueda ◽  
Moritake Higa ◽  
Hideaki Tanaka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
High Fat Diet ◽  
Diabetic Mice ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Abstract Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

scholarly journals Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaoqing Ma ◽  
Wenhua Du ◽  
Shanshan Shao ◽  
Chunxiao Yu ◽  
Lingyan Zhou ◽  
...  
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Liver Weight ◽  
Chow Diet ◽  
High Fat ◽  
Western Blots ◽  
Nonalcoholic Fatty Liver ◽  
Expression Levels

Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27%) and liver triglycerides (314.75%) compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease.

Abstract 313: KLF5 Plays an Important Role in Endoplasmic Reticulum Stress Response in both Cardiovascular and Metabolic System

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kosei Eguchi ◽  
Ichiro Manabe ◽  
Hua Shen ◽  
Yumiko Ohishi ◽  
Katsuhito Fujiu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Endoplasmic Reticulum ◽  
Cardiovascular Diseases ◽  
Er Stress ◽  
High Fat Diet ◽  
High Fat ◽  
Β Cells ◽  
Stress Markers ◽  
Insulin Expression ◽  
Metabolic Systems

We have previously shown that the transcription factor KLF5 plays an important role in cardiovascular diseases. KLF5 heterozygous knockout ( KLF5 +/− ) mice exhibited much less neointima formation in vascular injury models and less severe cardiac hypertrophy and fibrosis in the angiotensin II-loading model. We have also found that KLF5 is expressed in metabolic tissues, such as adipose tissue, pancreatic β-cell, and skeletal muscle. When KLF5 +/− mice were fed with high-fat diet, they were protected from metabolic syndrome. These findings demonstrate that KLF5 plays important roles in stress response in both cardiovascular and metabolic systems. To better understand how KLF5 responds to metabolic and inflammatory stress, we analyzed signaling pathways that activate KLF5. One such pathway was the unfolded protein response (UPR). Indeed, in KLF5 +/− mice fed with high-fat diet exhibited much less severe pancreatic islets remodeling, in which endoplasmic reticulum (ER) stress and UPR have been shown to play an essential role. To further analyze KLF5’s role in ER stress responses, we treated mouse MIN6 pancreatic β cells with palmitate as a model of lipotoxicity. Palmitate induced ER stress markers, CHOP, Bip and phosphor-eIF2α. The increases in ER stress markers were accompanied by induction of KLF5, while insulin expression was decreased. When ER stress was attenuated by 4-phenylbutyrate and tauroursodeoxycholate, the induction of KLF5 and the down regulation of insulin expression were significantly inhibited. When the KLF5 was knocked down with siRNA, the down regulation of insulin mRNA expression in response to palmitate was suppressed. These results demonstrate that KLF5 is a downstream effecter protein of ER stress in β-cells and is involved in insulin expression. We then analyzed it in the cardiovascular system. We found that KLF5 was also induced by ER stress in smooth muscle cells (SMCs). Moreover, interleukin-1, which is known to induce inflammatory genes in SMCs, activated KLF5 via ER stress. Results of the present study suggest that KLF5 responds to ER stress in both cardiovascular and metabolic systems and that this signaling pathway plays important roles in pathogenesis and progression of metabolic syndrome as well as cardiovascular diseases.

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