TY - JOUR
T1 - Mesencephalic astrocyte-derived neurotrophic factor as a urine biomarker for endoplasmic reticulum stress-related kidney diseases
AU - Kim, Yeawon
AU - Lee, Heedoo
AU - Manson, Scott R.
AU - Lindahl, Maria
AU - Evans, Bradley
AU - Miner, Jeffrey H.
AU - Urano, Fumihiko
AU - Chen, Ying Maggie
N1 - Funding Information:
We thank the Mouse Genetics Core, the Washington University Center for Kidney Disease Research (supported by National Institutes of Health [NIH] grant P30DK079333), and the Washington University Diabetes Research Center (supported by NIH grant P30 DK020579) for generation of transgenic mice and collecting urine and the Musculoskeletal Research Center Morphology Core (supported by NIH grant P30AR057235) for histology. We also thank Petra Gilmore, Yiling Mi, and Rose Connors for expert technical assistance and Dr. Reid Townsend for data analysis at the Washington University Proteomics Core for the Siteman Cancer Center (supported by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences and National Institute of General Medical Sciences grant P41 GM103422-35). We thank Dr. Mike Naldrett for expert technical assistance and discussions at the Proteomics and Mass Spectrometry Facility at Donald Danforth Plant Science Center. We thank Tatiana Danilova and Emmi Pakarinen at the University of Helsinki for conducting tunicamycin injection experiments on Manf−/− mice and wildtype littermates.
Funding Information:
Mice were housed in a facility supported by NIH grant C06RR015502. J.H.M. was supported by NIH grants R01DK078314 and R56DK100593. F.U. was supported by NIH grants R01DK067493, R01DK016746, P30DK020579, and UL1TR000448; Juvenile Diabetes Research Foundation grants 47-2012-760 and 17-2013-512; American Diabetes Association grant 1-12-CT-61, the Samuel E. Schechter Professorship, the Ellie White Foundation for Rare Genetic Disorders, and the Jack and J.T. Snow Scientific Research Foundation. Y.M.C. was supported by NIH grants K08DK089015, R03DK106451, and P30DK079333 (Pilot and Feasibility Study); a Halpin Foundation–American Society of Nephrology Research grant; Faculty Scholar Award MD-FR-2013-336 from the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital; Clinical Scientist Development Award 2015100 from the Doris Duke Charitable Foundation; a Career Development Award from the Nephrotic Syndrome Study Network; and an Early Career Development Award from the Central Society for Clinical and Translational Research.
Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2016
Y1 - 2016
N2 - Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin b2 protein-induced podocyte ER stress and AKI triggered by tunicamycin-or ischemiareperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.
AB - Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin b2 protein-induced podocyte ER stress and AKI triggered by tunicamycin-or ischemiareperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.
UR - http://www.scopus.com/inward/record.url?scp=85002301763&partnerID=8YFLogxK
U2 - 10.1681/ASN.2014100986
DO - 10.1681/ASN.2014100986
M3 - Article
C2 - 26940092
AN - SCOPUS:85002301763
VL - 27
SP - 2974
EP - 2982
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 10
ER -