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 - 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.
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U2 - 10.1126/scitranslmed.abj2109
DO - 10.1126/scitranslmed.abj2109
M3 - Article
C2 - 35947673
AN - SCOPUS:85136339868
SN - 1946-6234
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 657
ER -
