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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
JournalScience Translational Medicine
Volume14
Issue number657
DOIs
StatePublished - 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

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