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Research Article
DIABETIC KIDNEY DISEASE

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

Science Translational Medicine
10 Aug 2022
Vol 14, Issue 657

Predicting kidney disease progression

Patients with diabetes are at risk of kidney complications. Kobayashi et al. surveyed 25 circulating proteins in patient cohorts of both type 1 and type 2 diabetes and report that circulating neuroblastoma suppressor of tumorigenicity 1 (NBL1) protein is associated with 10-year risk for progression to end-stage kidney disease across multiple cohorts. This association was backed up by analysis of biopsied renal tissue. NBL1 may thus provide a noninvasive risk predictor for advanced diabetic kidney disease.

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.

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Supplementary Materials

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Materials and Methods
Figs. S1 to S9
Tables S1 to S4
References (97106)

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MDAR Reproducibility Checklist

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Science Translational Medicine
Volume 14 | Issue 657
August 2022

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Received: 27 April 2021
Accepted: 20 July 2022

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Acknowledgments

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.
Author contributions: H.K. contributed to design of the study, contributed to the proteomic data collection in the Joslin Kidney Study, performed data analysis, and wrote the manuscript. E.S., Z.I.M.D., K.O., K.I., and B.K. contributed to the collection of data in the Joslin Kidney study, implementation of experiments/measurements, and analysis of data and reviewed the manuscript. R.G.N., H.C.L., and P.J.S. were responsible for the design and implementation of the Pima Indian Study, contributed to the proteomic data collection in the Pima Indian Study, performed data analysis, interpreted the results, and reviewed and edited the manuscript. P.C.W. and B.D.H. analyzed and interpreted the results of snRNA-seq and helped edit the manuscript. H.S.B., J.M.W., and K.L.D. were responsible for the immunostaining studies of kidney biopsies and helped interpret results and edit the manuscript. F.D., A.P., and P.F. designed and performed experiments in vitro, interpreted the results, and reviewed the manuscript. D.C. performed NBL1 atlas immunostaining. B.N. reviewed and interpreted the immunostaining results and reviewed the manuscript. M.A.N., A.D., and M.M. interpreted the results and helped edit the manuscript. A.G. assisted in the statistical analyses and reviewed the manuscript. A.S.K. designed the study, supervised the study implementation, and planned and contributed to the data analysis, interpretation of the results, and manuscript writing.
Competing interests: A.S.K. provided consulting for Lilly and Janssen. He is an inventor of the U.S. pending patent application # WO 2022031920A2, title “End Stage Renal Biomarker Panel.” P.F. and F.D. hold equity and are consultant for Nephris Inc. and are co-inventors of the U.S. pending patent application # 63/226,125 titled “Methods for treating diabetic kidney disease and glomerular disease.” B.H. holds equity in Chinook Therapeutics and provided consulting for Janssen, Chinook Therapeutics, Pfizer, and Enyo Pharma. The other authors state that they have no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Individual proteomics data may become available for collaborative research from A.S.K. and R.N. upon completion of a data transfer agreement.

Authors

Affiliations

Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Division of Nephrology, Hypertension, and Endocrinology, Nihon University School of Medicine, Tokyo 173-8610, Japan.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Helen C. Looker
Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ 85014, USA.
Roles: Conceptualization, Data curation, Formal analysis, Methodology, and Validation.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Formal analysis, Resources, Software, and Writing - review & editing.
Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università di Milano and Endocrinology Division ASST Sacco-FBF, Milan 20121, Italy.
Roles: Investigation, Project administration, Resources, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ 85014, USA.
CHU Poitiers, University of Poitiers, Inserm, Clinical Investigation Center CIC1402, Poitiers 86000, France.
Roles: Conceptualization, Formal analysis, Validation, and Visualization.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Formal analysis, Investigation, and Methodology.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Roles: Investigation, Methodology, Resources, and Validation.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Conceptualization, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, and Writing - review & editing.
Bozena Krolewski
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Investigation, Validation, and Writing - review & editing.
Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA.
Roles: Investigation, Methodology, Resources, Validation, Visualization, and Writing - original draft.
Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università di Milano and Endocrinology Division ASST Sacco-FBF, Milan 20121, Italy.
Roles: Investigation, Resources, and Visualization.
Department of Medicine and Surgery, Unit of Pathology, University of Parma, Parma 43126, Italy.
Roles: Investigation, Resources, and Validation.
Andrzej Galecki
Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109-2029, USA.
Roles: Conceptualization, Formal analysis, Methodology, Software, Visualization, and Writing - review & editing.
Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, St. Louis 63110, USA.
Roles: Data curation, Formal analysis, Investigation, Resources, Software, Validation, Visualization, and Writing - review & editing.
Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98109, USA.
Role: Writing - review & editing.
Department of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
Roles: Investigation, Resources, Validation, and Writing - review & editing.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Role: Writing - review & editing.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Conceptualization and Writing - review & editing.
Division of Nephrology, Department of Medicine, Washington University in Saint Louis School of Medicine, St. Louis, MO 63110, USA.
Roles: Resources, Visualization, and Writing - review & editing.
Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46225, USA.
Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, and Supervision.
Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università di Milano and Endocrinology Division ASST Sacco-FBF, Milan 20121, Italy.
Nephrology Division, Boston Children’s Hospital, Boston, MA 02115, USA.
Roles: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ 85014, USA.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Roles: Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.

Funding Information

American Diabetes Association: Clinical Science Award 1-08-CR-42
JDRF: 5-CDA-2015-89-A-B
Mary K. Iacocca Fellowship
Sunstar Foundation: Hiroo Kaneda Scholarship
Italian Ministry of Health: RF-2016-02362512
Japan Society for the Promotion of Science: Overseas Research Fellowship
Novo Nordisk Fondendation: NNF14OC0013659
NIH DERC grant: P30 DK036836
Intramural Research Program of the NIH NIDDK
EFSD/JDRF/Lilly Programme 2019
Fondazione Invernizzi

Notes

*
Corresponding author. Email: [email protected] (R.G.N.); [email protected] (A.S.K.)

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