Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease
Yeawon Kim, … , Anthony J. Bleyer, Ying Maggie Chen
Yeawon Kim, … , Anthony J. Bleyer, Ying Maggie Chen
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e92896. https://doi.org/10.1172/jci.insight.92896.
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Research Article Nephrology

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

Abstract

ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress–mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress–induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion–induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.

Authors

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

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Figure 6

Detection of CRELD2 in the urine from human ADTKD-UMOD patients caused by UMOD mutations.

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Detection of CRELD2 in the urine from human ADTKD-UMOD patients caused b...
(A) Masson’s trichrome and PAS staining of paraffin kidney sections from ADTKD patients carrying UMOD mutation p.H177-R185 del or p.W202S, as well as from normal kidneys after nephrectomy. Scale bar: 40 μm. Arrowheads indicate tbular dilation, tubular atrophy with tubular basement membrane thickening. Arrow indicates interstitial inflammatory monocyte infiltration. (B) Representative IF images of human renal biopsies obtained from patients with p.H177-R185 del or p.W202S UMOD mutation and from normal kidneys, stained for CRELD2 (green) and uromodulin (red) with a nuclear counterstain (Hoechst 33342, blue). Scale bar: 40 μm. Arrows indicate enrichment of native uromodulin at the apical membrane of TAL cells. (C and D) Crude urine samples from human ADTKD-UMOD patients harboring H177-R185 del (C) or other disease-causing mutations including C106F, D172H, V93-G97delinsAASC, R178P, and G103C (D), as well as from genetically unaffected family members, were analyzed by WB for CRELD2 excretion. The urinary CRELD2 excretion was normalized to 10 μg of urine Cr excretion. The control and patient numbers listed in C–D corresponded to the same numbers in Table 2. (E) Dot plot representation of urine CRELD2/Cr values measured by the ELISA in the above 17 ADTKD-UMOD patients harboring various UMOD mutations and 7 genetically unaffected controls. Data represent mean ± SEM, *P < 0.05 by 2-tailed t test. PAS, periodic acid-Schiff; CRELD2, cysteine-rich with EGF-like domains 2; ADTKD, autosomal dominant tubulointerstitial kidney disease.