Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

Hiroki Kobayashi; Helen C. Looker; Eiichiro Satake; Francesca D’Addio; Jonathan M. Wilson; Pierre Jean Saulnier; Zaipul I. Md Dom; Kristina O’Neil; Katsuhito Ihara; Bozena Krolewski; Hannah S. Badger; Adriana Petrazzuolo; Domenico Corradi; Andrzej Galecki; Parker C. Wilson; Behzad Najafian; Michael Mauer; Monika A. Niewczas; Alessandro Doria; Benjamin D. Humphreys; Kevin L. Duffin; Paolo Fiorina; Robert G. Nelson; Andrzej S. Krolewski

doi:10.1126/scitranslmed.abj2109

Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

Hiroki Kobayashi, Helen C. Looker, Eiichiro Satake, Francesca D’Addio, Jonathan M. Wilson, Pierre Jean Saulnier, Zaipul I. Md Dom, Kristina O’Neil, Katsuhito Ihara, Bozena Krolewski, Hannah S. Badger, Adriana Petrazzuolo, Domenico Corradi, Andrzej Galecki, Parker C. Wilson, Behzad Najafian, Michael Mauer, Monika A. Niewczas, Alessandro Doria, Benjamin D. HumphreysKevin L. Duffin, Paolo Fiorina, Robert G. Nelson, Andrzej S. Krolewski

Pediatric Nephrology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Circulating proteins associated with transforming growth factor–β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

Original language	English (US)
Journal	Science Translational Medicine
Volume	14
Issue number	657
DOIs	https://doi.org/10.1126/scitranslmed.abj2109
State	Published - Aug 10 2022

Bibliographical note

Funding Information:
We acknowledge grant support from the National Institutes of Health (NIH) (DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) to H.K.; and The Mary K. Iacocca Fellowship, the Sunstar Foundation, Japan (Hiroo Kaneda Scholarship), and the Foundation for Growth Science from Japan to E.S. This research was also supported by the American Diabetes Association (Clinical Science Award 1-08-CR-42) to R.G.N.; the Intramural Research Program of the NIH NIDDK to R.G.N., H.C.L., and P.J.S.; NIH DERC grant (P30 DK036836) to Joslin Diabetes Center; the Fondazione Invernizzi to P.F. and F.D.; the Italian Ministry of Health (RF-2016-02362512) to P.F.; and the EFSD/JDRF/Lilly Programme 2019 to F.D

Funding Information:
Funding: We acknowledge grant support from the National Institutes of Health (NIH)

Funding Information:
(DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship)

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1126/scitranslmed.abj2109

Find It

Find It at U of M Libraries

Cite this

Kobayashi, H., Looker, H. C., Satake, E., D’Addio, F., Wilson, J. M., Saulnier, P. J., Md Dom, Z. I., O’Neil, K., Ihara, K., Krolewski, B., Badger, H. S., Petrazzuolo, A., Corradi, D., Galecki, A., Wilson, P. C., Najafian, B., Mauer, M., Niewczas, M. A., Doria, A., ... Krolewski, A. S. (2022). Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes. Science Translational Medicine, 14(657). https://doi.org/10.1126/scitranslmed.abj2109

Kobayashi, H, Looker, HC, Satake, E, D’Addio, F, Wilson, JM, Saulnier, PJ, Md Dom, ZI, O’Neil, K, Ihara, K, Krolewski, B, Badger, HS, Petrazzuolo, A, Corradi, D, Galecki, A, Wilson, PC, Najafian, B, Mauer, M, Niewczas, MA, Doria, A, Humphreys, BD, Duffin, KL, Fiorina, P, Nelson, RG & Krolewski, AS 2022, 'Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes', Science Translational Medicine, vol. 14, no. 657. https://doi.org/10.1126/scitranslmed.abj2109

@article{250e00495cfd481ea45763b8d8a547e7,

title = "Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes",

abstract = "Circulating proteins associated with transforming growth factor–β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.",

author = "Hiroki Kobayashi and Looker, {Helen C.} and Eiichiro Satake and Francesca D{\textquoteright}Addio and Wilson, {Jonathan M.} and Saulnier, {Pierre Jean} and {Md Dom}, {Zaipul I.} and Kristina O{\textquoteright}Neil and Katsuhito Ihara and Bozena Krolewski and Badger, {Hannah S.} and Adriana Petrazzuolo and Domenico Corradi and Andrzej Galecki and Wilson, {Parker C.} and Behzad Najafian and Michael Mauer and Niewczas, {Monika A.} and Alessandro Doria and Humphreys, {Benjamin D.} and Duffin, {Kevin L.} and Paolo Fiorina and Nelson, {Robert G.} and Krolewski, {Andrzej S.}",

note = "Funding Information: We acknowledge grant support from the National Institutes of Health (NIH) (DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) to H.K.; and The Mary K. Iacocca Fellowship, the Sunstar Foundation, Japan (Hiroo Kaneda Scholarship), and the Foundation for Growth Science from Japan to E.S. This research was also supported by the American Diabetes Association (Clinical Science Award 1-08-CR-42) to R.G.N.; the Intramural Research Program of the NIH NIDDK to R.G.N., H.C.L., and P.J.S.; NIH DERC grant (P30 DK036836) to Joslin Diabetes Center; the Fondazione Invernizzi to P.F. and F.D.; the Italian Ministry of Health (RF-2016-02362512) to P.F.; and the EFSD/JDRF/Lilly Programme 2019 to F.D Funding Information: Funding: We acknowledge grant support from the National Institutes of Health (NIH) Funding Information: (DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = aug,

day = "10",

doi = "10.1126/scitranslmed.abj2109",

language = "English (US)",

volume = "14",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "657",

}

TY - JOUR

T1 - Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

AU - Kobayashi, Hiroki

AU - Looker, Helen C.

AU - Satake, Eiichiro

AU - D’Addio, Francesca

AU - Wilson, Jonathan M.

AU - Saulnier, Pierre Jean

AU - Md Dom, Zaipul I.

AU - O’Neil, Kristina

AU - Ihara, Katsuhito

AU - Krolewski, Bozena

AU - Badger, Hannah S.

AU - Petrazzuolo, Adriana

AU - Corradi, Domenico

AU - Galecki, Andrzej

AU - Wilson, Parker C.

AU - Najafian, Behzad

AU - Mauer, Michael

AU - Niewczas, Monika A.

AU - Doria, Alessandro

AU - Humphreys, Benjamin D.

AU - Duffin, Kevin L.

AU - Fiorina, Paolo

AU - Nelson, Robert G.

AU - Krolewski, Andrzej S.

N1 - Funding Information: We acknowledge grant support from the National Institutes of Health (NIH) (DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) to H.K.; and The Mary K. Iacocca Fellowship, the Sunstar Foundation, Japan (Hiroo Kaneda Scholarship), and the Foundation for Growth Science from Japan to E.S. This research was also supported by the American Diabetes Association (Clinical Science Award 1-08-CR-42) to R.G.N.; the Intramural Research Program of the NIH NIDDK to R.G.N., H.C.L., and P.J.S.; NIH DERC grant (P30 DK036836) to Joslin Diabetes Center; the Fondazione Invernizzi to P.F. and F.D.; the Italian Ministry of Health (RF-2016-02362512) to P.F.; and the EFSD/JDRF/Lilly Programme 2019 to F.D Funding Information: Funding: We acknowledge grant support from the National Institutes of Health (NIH) Funding Information: (DK041526, DK110350, and DK126799) to A.S.K.; the Novo Nordisk Foundation grant NNF14OC0013659 (PROTON) to A.S.K.; The Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

PY - 2022/8/10

Y1 - 2022/8/10

N2 - Circulating proteins associated with transforming growth factor–β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

AB - Circulating proteins associated with transforming growth factor–β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

UR - http://www.scopus.com/inward/record.url?scp=85136339868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136339868&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.abj2109

DO - 10.1126/scitranslmed.abj2109

M3 - Article

C2 - 35947673

AN - SCOPUS:85136339868

VL - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 657

ER -

Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this