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JCI Insight. 2017 Dec 7;2(23). pii: 92896. doi: 10.1172/jci.insight.92896. [Epub ahead of print]

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

Author information

1
Division of Nephrology, Department of Internal Medicine.
2
Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
3
Division of Urology, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
4
Section of Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
5
Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut.
6
RTE Professor of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Arkana Laboratories, Little Rock, Arkansas, USA.
8
Institute for Inherited Metabolic Disorders, Charles University in Prague, Prague, Czech Republic.
9
Clinical Epidemiology Research Center, Veterans Affairs Medical Center, West Haven, Connecticut, USA.

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.

KEYWORDS:

Cell stress; Nephrology

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