The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes

Ozawa, Kentaro; Miyazaki, Mutsuko; Matsuhisa, Munehide; Takano, Katsura; Nakatani, Yoichiro; Hatazaki, Masahiro; Tamatani, Takashi; Yamagata, Kazuya; Miyagawa, Jun Ichiro; Kitao, Yasuko; Hori, Osamu; Yamasaki, Yoshimitsu; Ogawa, Satoshi

doi:10.2337/diabetes.54.3.657

Cited by 186 publications

(137 citation statements)

References 38 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…28 Systemic overexpression of ORP150 improved insulin intolerance in a murine model of spontaneous diabetes. 29 Furthermore, transgenic mice overexpressing ORP150 were more resistant to renal ischemia/reperfusion injury. 19 Taken together, these studies along with our study suggest the benefits of preconditioning with ER stress, namely that preconditioning enhances the adaptive UPR to protect the cell more effectively against the pathogenic environment via the maintenance of ER function.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

103

View full text Add to dashboard Cite

Accumulating evidence suggests a pathophysiologic role of endoplasmic reticulum (ER) stress in kidney disease. This study investigated the potential of therapeutic approaches targeting ER stress in the anti-Thy1 model of mesangioproliferative glomerulonephritis in rats. Immunohistochemistry and Western blotting showed a time-dependent increase in the expression of the ER stress-inducible chaperones glucose-regulated protein 78 (GRP78) and oxygen-related protein 150 in isolated glomeruli, especially in the glomerular epithelial cells and mesangial cells, after induction of anti-Thy1 nephritis. For evaluation of whether preconditioning with ER stress ameliorates the severity of disease, rats were pretreated with a subnephritogenic dose of the ER stress inducer tunicamycin or thapsigargin for 4 d before disease was induced. Although preconditioning with ER stress had no effect on the degree of disease induction, it strongly ameliorated the manifestations of disease, evidenced by marked reductions in microaneurysm formation, mesangial proliferation, and adhesion of Bowman's capsule to the glomerular tuft. This improvement in histologic damage was associated with reduced proteinuria (39.4 Ϯ 10.5 versus 126.1 Ϯ 18.1 mg/d; P Ͻ 0.01) and with attenuated increases in glucose-regulated protein 78 and oxygen-related protein 150 expression. Of note, pretreatment with tunicamycin or thapsigargin decreased the excessive ER stress-induced intracellular signaling observed in anti-Thy1 nephritis. In conclusion, preconditioning with ER stress ameliorates the severity of disease in rats with anti-Thy1 nephritis. These findings suggest the possibility of therapeutic approaches targeting ER stress in mesangioproliferative glomerulonephritis.

show abstract

Section: Discussionmentioning

confidence: 99%

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

103

View full text Add to dashboard Cite

show abstract

“…Both 4-PBA and UDCA have been successfully used to alleviate ER stress, restore glucose tolerance and improve insulin sensitivity. 20,45,46 However, the effect of 4-PBA or UDCA on ER stress in DN remains un-elucidated. Our findings have shown that both UDCA and 4-PBA could suppress the UPR in podocytes in vitro, as evidenced by the decreased protein expression of BiP, phospho-PERK, phospho-IRE1α and cleaved ATF-6, which were upregulated by HG, suggesting that UDCA and 4-PBA could inhibit HG-induced ER stress in podocytes.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Wang

Chen

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded and/or unfolded proteins in ER membranes, is involved in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the role of ER stress inhibitors ursodeoxycholic acid (UDCA) and 4-phenylbutyrate (4-PBA) in the treatment of DN in db/db mice. Findings have revealed that diabetic db/db mice were more hyperglycemic than their non-diabetic controls, and exhibited a marked increase in body weight, water intake, urine volume, fasting plasma glucose, systolic blood pressure, glucose and insulin tolerance. UDCA (40 mg/kg/day) or 4-PBA (100 mg/kg/day) treatment for 12 weeks resulted in an improvement in these biochemical and physical parameters. Moreover, UDCA or 4-PBA intervention markedly decreased urinary albuminuria and attenuated mesangial expansion in diabetic db/db mice, compared with db/db mice treated with vehicle. These beneficial effects of UDCA or 4-PBA on DN were associated with the inhibition of ER stress, as evidenced by the decreased expression of BiP, phospho-IRE1α, phospho-eIF2α, CHOP, ATF-6 and spliced X-box binding protein-1 in vitro and in vivo. UDCA or 4-PBA prevented hyperglycemia-induced or high glucose (HG)-induced apoptosis in podocytes in vivo and in vitro via the inhibition of caspase-3 and caspase-12 activation. Autophagy deficiency was also seen in glomeruli in diabetic mice and HG-incubated podocytes, exhibiting decreased expression of LC3B and Beclin-1, which could be restored by UDCA or 4-PBA treatment. Taken together, our results have revealed an important role of ER stress in the development of DN, and UDCA or 4-PBA treatment may be a potential novel therapeutic approach for the treatment of DN.

show abstract

“…There are a myriad of compounds ( Table 1) that improve ER folding capacity such as the chemical chaperones 4-phenylbutyric acid (PBA), taurine-conjugated ursodeoxycholic acid (TUDCA) and ER chaperones that reduce ER stress and improve insulin action and sensitivity (Ozawa et al 2005, Ozcan et al 2006. Small-molecule chemical chaperones such as TUDCA and 4-PBA are suspected to enhance either protein secretion or the folding capacity of the ER (Park & Ozcan 2013).…”

Section: Therapeutic Implications Of Er Stress Modulatorsmentioning

confidence: 99%

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Zhuang¹,

Forbes²

2014

Journal of Endocrinology

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts. Key Words" endoplasmic reticulum stress " diabetic nephropathy

show abstract

The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes

Cited by 186 publications

References 38 publications

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Contact Info

Product

Resources

About