Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Hassan, Hossam M.; Tian, Xuefei; Inoue, Kazunori; Chai, Nathan; Liu, Chang; Soda, Kunitsugu; Moeckel, Gilbert; Tufró, Alda; Lee, Ann-Hwee; Somlo, Stefan; Fedeles, Sorin V.; Ishibe, Shuta

doi:10.1681/asn.2015020191

Cited by 37 publications

(43 citation statements)

References 42 publications

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“…described (75). The number of foot processes was divided by the total length of glomerular basement membrane regions in each electron microscopic image (76).…”

Section: Discussionmentioning

confidence: 99%

“…Images were taken by an Andor CSU-WDi spinning disc confocal microscope equipped with a Nikon Ti-E CFI Plan Apochromat Lambda ×60 oil immersion objective for immunofluorescence analysis, and images were processed using NIH ImageJ software (version 1.51H) or Adobe Photoshop CS 2014. For quantification of podocyte number, WT1-positive nuclei were counted in each glomeruli (77). For quantification of changes in actin cytoarchitecture of primary podocytes, podocytes stained with phalloidin were Figure 11.…”

Section: Discussionmentioning

confidence: 99%

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Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Inoue¹,

Gan²,

Ciarleglio³

et al. 2019

Journal of Clinical Investigation

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“…described (75). The number of foot processes was divided by the total length of glomerular basement membrane regions in each electron microscopic image (76).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Inoue¹,

Gan²,

Ciarleglio³

et al. 2019

Journal of Clinical Investigation

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“…This appears to be a unique feature of collecting ducts because we had previously found that inactivating Sec63 in podocytes resulted in activation of at least the Ire1a-Xbp1 branch of UPR, which served as a compensatory mechanism to prevent podocyte dysfunction and loss. 25 Similarly, inactivation of Sec63 using Cdh16(Ksp)-Cre, which targets mTAL, DCT, and the collecting duct, resulted in activation of the Ire1a-Xbp1 pathway detectable in whole kidney lysates. Concomitant inactivation of Xbp1 resulted in worsening kidney cyst formation, corroborating the adaptive value of UPR activation in this model as well.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of Sec63, activation of Ire1a-Xbp1 and its transcriptional targets has an adaptive role in supporting maturation of polycystin-1 and, by inference, other Sec63 client proteins. 18,25,26 In this study, we set out to examine the effects of collecting tubule deletion of Sec63 and the Ire1a-Xbp1 pathway on kidney homeostasis and function. Surprisingly, we found that Sec63 inactivation in collecting ducts did not result in activation of the Ire1a-Xbp1 pathway or a discernible phenotype, but that concomitant inactivation of Ire1a or Xbp1 along with Sec63 caused a severe, progressive inflammatory and fibrotic response leading to kidney dysfunction.…”

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confidence: 99%

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Ishikawa¹,

Fedeles²,

Marlier³

et al. 2019

JASN

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Background SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1a-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model. MethodsWe explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1a, specifically in the collecting ducts of neonatal mice. ResultsThe later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1a-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1a in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1a. ConclusionsIn the absence of Sec63, basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.

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“…RhoGDI signaling may provide targets for HER2-positive breast cancer therapy. X-box binding protein 1 (XBP1) is the main regulator of endoplasmic reticulum stress (ERS) with basic lucien zipper structure [41] [42] . A large number of studies have shown that XBP1 is highly expressed in a variety of malignant tumor cells, and can promote the hypoxic survival of tumor cells and induce tumor metastasis and drug resistance [43] .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of luminal A and HER2-positive breast cancer based on DIA quantitative proteomics and bioinformatics analysis techniques

Wu¹,

Zhang²,

Liang³

et al. 2020

Preprint

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Background: Breast cancer has common tumor biological characteristics, but different characteristics also exist among different subtypes. Different treatment strategies have been adopted for different subtypes at present, but there are still many problems. Thus, an-depth study on the heterogeneity of different types of breast cancer will help to identify new diagnostic therapeutic targets and solve the existing problems of individualized treatment for breast cancer.Methods: In this study proteins of HER2-positive breast cancer, luminal A breast cancer, and para-cancer tissues were quantified based on data independent acquisition (DIA) proteomics technology, and the differentially expressed proteins (DEPs) were screened and analyzed by IPA software and the database among the luminal A (LA ) versus para-cancer tissues (PT) and HER2 versus LA groups.Results: There were 264 up- and 123 down-regulated proteins in the LA versus PT groups. PD-1 and PD-L1 cancer immunotherapy pathways were significantly inhibited, and XBP1 was predicted to be the strongest activator. MTOR was predicted to be the strongest inhibitor. The DEPs were significantly associated with “Cancer” and “Organismal Injury and Abnormalities.” There were 134 up- and 286 down-regulated proteins in the HER2 versus LA groups. Signaling by rho family GTPases was significantly inhibited. XBP1 was predicted to be the strongest activator. TGFB1 was predicted to be the strongest inhibitor. The DEPs were significantly associated with “Cancer,” “Endocrine System Disorders,” and “Organismal Injury and Abnormalities.”Conclusion: Luminal A breast cancer may be insensitive to PD-1 and PD-L1 inhibitors. Signaling by rho family GTPases and RhoGDI signaling play a unique role in the proliferation and metastasis of luminal A and HER2-positive breast cancer, respectively. XBP1 is a promising new target for the treatment of breast cancer, and TGFB1 may play different biological roles in HER2-positive and luminal A breast cancer.

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Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

Cited by 37 publications

References 42 publications

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Heterogeneity of luminal A and HER2-positive breast cancer based on DIA quantitative proteomics and bioinformatics analysis techniques

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