Endoplasmic Reticulum Stress in the Diabetic Kidney,  the Good, the Bad and the Ugly

Cunard, Robyn

doi:10.3390/jcm4040715

Cited by 59 publications

(41 citation statements)

References 212 publications

(270 reference statements)

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“…During its early phase, the UPR either refolds the accumulated unfolded proteins or degrades them via the ubiquitin-proteasome pathway 54 . When the unfolded protein and cellular damage exceed a threshold and the chronic cell stress is not relieved, proapoptotic responses are initiated and cell death ultimately ensues 55, 56 . Although our studies were not designed to assess the role of ROS in promoting kidney injury, we found that 4-HNE, an indicator of lipid peroxidation and oxidative stress, was markedly upregulated in hypertensive kidneys of GK-AC rats compared to normotensive kidneys of the same diabetic rats or hypertensive kidneys of Wistar-AC rats after 8 weeks of AC.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

et al. 2017

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Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162±11 and 87±2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure (BP) in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 wks of AC, BP above the AC (and in the right kidney) increased from 109±1 to 152±5 mmHg in GK rats and from 106±4 to 141±5 mmHg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared to left kidneys (diabetes only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid (TUDCA) for 6 wks reduced BP (135±4 vs 151±4 mmHg), albumin excretion, ER and oxidative stress, glomerular injury, while increasing GFR in hypertensive-diabetic kidneys. These results suggest that diabetes and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress.

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Section: Discussionmentioning

confidence: 99%

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

et al. 2017

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“…Thus, inhibiting EGFR activation may also serve as a therapeutic target for DN. In addition, Endoplasmic reticulum (ER) stress, with misfolded and/or unfolded proteins in ER membranes, has been shown to mediate DN development and progression [10]. The crosstalk between ER stress and ROS production is well established in cancer biology, in which increasing ROS induces ER stress to trigger cancer cell apoptosis [11–13].…”

Section: Introductionmentioning

confidence: 99%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.

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“…TUDCA) has been shown to improve symptoms of renal diseases. There are a number of comprehensive reviews covering ER stress and renal damage, and therefore, this will not be discussed here (Cunard, ; Taniguchi & Yoshida, ; Wang et al . ).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress in the pathogenesis of hypertension

Young

2017

Experimental Physiology

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What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease.

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Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

Cited by 59 publications

References 212 publications

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Endoplasmic reticulum stress in the pathogenesis of hypertension

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