Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

Park, Sun-Ji; Manson, Scott R.; Molina, C.; Kidd, Kendrah; Thiessen-Philbrook, Heather; Perry, Rebecca; Liapis, Helen; Kmoch, Stanislav; Parikh, Chirag R.; Bleyer, Anthony J.; Chen, Ying Maggie

doi:10.1172/jci.insight.92896

Cited by 33 publications

(36 citation statements)

References 49 publications

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“…Finally, CRELD2 is easily detected in unconcentrated urine from human ADTKD- UMOD patients, whereas urinary CRELD2 excretion is absent from all tested genetically unaffected controls by ELISA assay (Figure 2B). These results demonstrate the superb ability of CRELD2 to discriminate between controls and ADTKD patients with tubular ER stress [47]. …”

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 77%

“…Recently, we have identified mesencephalic astrocyte-derived neurotrophic factor (MANF) and cysteine-rich with EGF-like domains 2 (CRELD2) as urinary ER stress biomarkers [46, 47]. …”

Section: Discovery Of Urinary Er Stress Biomarkers In Er Stress-mediamentioning

confidence: 99%

“…In addition, both ER stressors increase CRELD2 secretion into the culture medium by mouse podocytes, whereas in the absence of ER stress, there is little CRELD2 secretion [47]. These data suggest that upregulation and secretion of CRELD2 induced by ER stress is not a cell-type-specific response.…”

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

“…Furthermore, in our podocyte ER stress-induced NS mouse model carrying the C321R-LAMB2 mutation in podocytes, CRELD2 are upregulated at both transcriptional and translational levels in the mutant podocytes compared with control podocytes. Most importantly, CRELD2 is easily detected in unprocessed urine specimens from C321R mutants, but not from control littermates, at the early stage of NS [47]. …”

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

“…We also investigated CRELD2 as a urinary biomarker for detecting tubular ER stress in ADTKD- UMOD , a prototypical tubular ER stress disease [47]. Co-immunofluorescence (IF) staining of CRELD2 and uromodulin in human kidney biopsies showed that native uromodulin is enriched at the apical membrane of TAL cells (arrows, Figure 2A).…”

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

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Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

Park

Chen

2018

Pediatr Nephrol

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The advent of next-generation sequencing (NGS) in recent years has led to a rapid discovery of novel or rare genetic variants in human kidney cell genes, which is transforming the risk assessment, diagnosis, and treatment of kidney disease. Mutations may lead to protein misfolding, disruption of protein trafficking, and endoplasmic reticulum (ER) retention. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and unfolded protein response. Mutations in nephrin (NPHS1), podocin (NPHS2), laminin β2 (LAMB2), and α-actinin-4 (ACTN4) have been shown to induce ER stress in HEK293 cells and podocytes in hereditary nephrotic syndromes; various founder mutations in collagen IV α chains (COL4A) have been demonstrated to activate podocyte ER stress in collagen IV nephropathies; and mutations in uromodulin (UMOD) have been reported to trigger tubular ER stress in autosomal dominant tubulointerstitial kidney disease. Meanwhile, ER resident protein SEC63 may modify disease severity in autosomal dominant polycystic kidney disease. These findings underscore the importance of ER stress in the pathogenesis of monogenic kidney disease. Recently, we have identified mesencephalic astrocyte-derived neurotrophic factor (MANF) and cysteine-rich with EGF-like domains 2 (CRELD2) as urinary ER stress biomarkers in ER stress-mediated kidney diseases.

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Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 77%

“…Recently, we have identified mesencephalic astrocyte-derived neurotrophic factor (MANF) and cysteine-rich with EGF-like domains 2 (CRELD2) as urinary ER stress biomarkers [46, 47]. …”

Section: Discovery Of Urinary Er Stress Biomarkers In Er Stress-mediamentioning

confidence: 99%

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

Section: Creld2 As a Urine Er Stress Biomarker In Both Mouse Models Amentioning

confidence: 99%

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Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

Park

Chen

2018

Pediatr Nephrol

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CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development

Dennis

Edwards

Jackson

et al. 2020

Journal of Bone and Mineral Research

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Cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER)-resident chaperone highly activated under ER stress in conditions such as chondrodysplasias; however, its role in healthy skeletal development is unknown. We show for the first time that cartilage-specific deletion of Creld2 results in disrupted endochondral ossification and short limbed dwarfism, whereas deletion of Creld2 in bone results in osteopenia, with a low bone density and altered trabecular architecture. Our study provides the first evidence that CRELD2 promotes the differentiation and maturation of skeletal cells by modulating noncanonical WNT4 signaling regulated by p38 MAPK. Furthermore, we show that CRELD2 is a novel chaperone for the receptor lowdensity lipoprotein receptor-related protein 1 (LRP1), promoting its transport to the cell surface, and that LRP1 directly regulates WNT4 expression in chondrocytes through TGF-β1 signaling. Therefore, our data provide a novel link between an ER-resident chaperone and the essential WNT signaling pathways active during skeletal differentiation that could be applicable in other WNTresponsive tissues.

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Molecular characterization of the ER stress-inducible factor CRELD2

Hinaga,

Kandeel,

Oh-hashi

2024

Cell Biochem Biophys

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Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

Cited by 33 publications

References 49 publications

Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development

Molecular characterization of the ER stress-inducible factor CRELD2

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