Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis

2015 ◽  
Vol 308 (3) ◽  
pp. F226-F236 ◽  
Author(s):  
Hyosang Kim ◽  
Soo Young Moon ◽  
Joon-Seok Kim ◽  
Chung Hee Baek ◽  
Miyeon Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mouse Model ◽  
Er Stress ◽  
Heme Oxygenase ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Initiation Factor ◽  
Heme Oxygenase 1 ◽  
Compound C ◽  
Amp Activated Protein Kinase

It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.

AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition

2013 ◽  
Vol 304 (6) ◽  
pp. F686-F697 ◽  
Author(s):  
Jang Han Lee ◽  
Ji Hyun Kim ◽  
Ja Seon Kim ◽  
Jai Won Chang ◽  
Soon Bae Kim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Urinary Albumin ◽  
Heme Oxygenase 1 ◽  
Mesenchymal Transition ◽  
Compound C ◽  
Amp Activated Protein Kinase

The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-β (TGF-β), angiotensin II, aldosterone, high glucose, and urinary albumin are well-known causes of EMT and renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed EMT induced by the above agents in tubular epithelial cells. All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. Exposure of tubular cells to TGF-β (10 ng/ml), angiotensin II (1 μM), aldosterone (100 nM), high glucose (30 mM), and albumin (5 mg/ml) for 5 days induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ROS and NADPH oxidase 4 (Nox4) expression were increased, and antioxidants such as tiron and N-acetylcysteine inhibited EMT induction. Metformin (the best known clinical activator of AMPK) suppressed EMT induction through inhibition of ROS via induction of heme oxygenase-1 and endogenous antioxidant thioredoxin. An AMPK inhibitor (compound C) and AMPK small interfering RNA blocked the effect of metformin, and another AMPK activator [5-aminoimidazole-4-carboxamide-1β riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-β, angiotensin II, aldosterone, high glucose, and urinary albumin.

scholarly journals Palmitate Causes Endoplasmic Reticulum Stress and Apoptosis in Human Mesenchymal Stem Cells: Prevention by AMPK Activator

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5275-5284 ◽  
Author(s):  
Jun Lu ◽  
Qinghua Wang ◽  
Lianghu Huang ◽  
Huiyue Dong ◽  
Lingjing Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endoplasmic Reticulum ◽  
Mesenchymal Stem Cells ◽  
Protein Kinase ◽  
Er Stress ◽  
Human Mesenchymal Stem Cells ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Human Umbilical Cord ◽  
Amp Activated Protein Kinase

Abstract Elevated circulating saturated fatty acids concentration is commonly associated with poorly controlled diabetes. The highly prevalent free fatty acid palmitate could induce apoptosis in various cell types, but little is known about its effects on human mesenchymal stem cells (MSCs). Here, we report that prolonged exposure to palmitate induces human bone marrow-derived MSC (hBM-MSC) and human umbilical cord-derived MSC apoptosis. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cell apoptosis. Palmitate activated XBP1 splicing, elF2α (eukaryotic translation initiation factor 2α) phosphorylation, and CHOP, ATF4, BiP, and GRP94 transcription in hBM-MSCs. ERK1/2 and p38 MAPK phosphorylation were also induced by palmitate in hBM-MSCs. A selective p38 inhibitor inhibited palmitate activation of the ER stress, whereas the ERK1/2 inhibitors had no effect. The AMP-activated protein kinase activator aminoimidazole carboxamide ribonucleotide blocked palmitate-induced ER stress and apoptosis. These findings suggest that palmitate induces ER stress and ERK1/2 and p38 activation in hBM-MSCs, and AMP-activated protein kinase activator prevents the deleterious effects of palmitate by inhibiting ER stress and apoptosis.

scholarly journals Liraglutide via Activation of AMP-Activated Protein Kinase-Hypoxia Inducible Factor-1α-Heme Oxygenase-1 Signaling Promotes Wound Healing by Preventing Endothelial Dysfunction in Diabetic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiya Huang ◽  
Linlin Wang ◽  
Fanyu Qian ◽  
Xiong Chen ◽  
Haiping Zhu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Heme Oxygenase ◽  
Hypoxia Inducible Factor ◽  
Heme Oxygenase 1 ◽  
Diabetic Wound ◽  
Hypoxia Inducible Factor 1Α ◽  
Diabetic Wound Healing ◽  
Amp Activated Protein Kinase

Background/Aims: Diabetic foot ulcers (DFUs) present a major challenge in clinical practice, and hyperglycemia-induced angiogenesis disturbance and endothelial dysfunction likely exacerbate DFUs. The long-acting glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira) is a potential activator of AMP-activated protein kinase (AMPK) that appears to enhance endothelial function and have substantial pro-angiogenesis and antioxidant stress effects. Therefore, in this study, we aimed to investigate whether the protective role of Lira in diabetic wound healing acts against the mechanisms underlying hyperglycemia-induced endothelial dysfunction and angiogenesis disturbance.Methods: Accordingly, db/db mice were assessed after receiving subcutaneous Lira injections. We also cultured human umbilical vein endothelial cells (HUVECs) in either normal or high glucose (5.5 or 33 mM glucose, respectively) medium with or without Lira for 72 h.Results: An obvious inhibition of hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance was observed; follow by a promotion of diabetic wound healing under Lira treatment combined with restored hyperglycemia-impaired AMPK signaling pathway activity. AMPKα1/2 siRNA and Compound C (Cpd C), an inhibitor of AMPK, abolished both Lira-mediated endothelial protection and pro-angiogenesis action, as well as the diabetic wound healing promoted by Lira. Furthermore, hypoxia inducible factor-1α (Hif-1α; transcription factors of AMPK substrates) knockdown in HUVECs and db/db mice demonstrated that Lira activated AMPK to prevent hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance, with a subsequent promotion of diabetic wound healing that was Hif-1α–heme oxygenase-1 (HO-1) axis-dependent. Taken together, these findings reveal that the promotion of diabetic wound healing by Lira occurs via its AMPK-dependent endothelial protection and pro-angiogenic effects, which are regulated by the Hif-1α–HO-1 axis.

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