Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease
Jiahao Liu, Viji Nair, Yiyang Zhao, Dong‐Yuan Chang, Christine P. Limonte, Nisha Bansal, Damian Fermin, Felix Eichinger, Emily C. Tanner, Keith Bellovich, Susan Steigerwalt, Zeenat Bhat, Jennifer Hawkins, Lalita Subramanian, Sylvia E. Rosas, John R. Sedor, Miguel Vasquez, Sushrut S. Waikar, Markus Bitzer, Subramaniam Pennathur, Frank C. Brosius, Ian H. de Boer, Min Chen, Matthias Kretzler, Wenjun Ju, for the Kidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group, Kidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group, Richard Knight, Stewart H. Lecker, Isaac E. Stillman, Steve Bogen, Afolarin Amodu, Titlayo Ilori, Shana Maikhor, Insa M. Schmidt, Laurence H. Beck, Joel Henderson, Ingrid Onul, Ashish Verma, Sushrut S. Waikar, Gearoid M. McMahon, M. Todd Valerius, Sushrut S. Waikar, Astrid Weins, Mia R. Colona, Anna Greka, Nir Hacohen, Paul Hoover, Jamie L. Marshall, Mark P. Aulisio, Yijiang M. Chen, Andrew Janowczyk, Catherine Jayapandian, Vidya Sankar Viswanathan, William S. Bush, Dana C. Crawford, Anant Madabhushi, Lakeshia Bush, Leslie Cooperman, Agustin Gonzalez‐Vicente, Leal Herlitz, Stacey E. Jolly, Jane Nguyen, John O’Toole, Ellen M. Palmer, Emilio D. Poggio, John R. Sedor, Dianna Sendrey, Kassandra Spates-Harden, Jonathan J. Taliercio, P. M. Bjørnstad, Laura Pyle, Carissa Vinovskis, Paul S. Appelbaum, Jonathan Barasch, Andrew S. Bomback, Pietro A. Canetta, Vivette D. D’Agati, Krzysztof Kiryluk, Satoru Kudose, Karla Mehl, Ning Shang, Olivia Balderes, Shweta Bansal, Theodore Alexandrov, Helmut G. Rennke, Tarek M. El‐Achkar, Daria Barwinska, Sharon B. Bledsoe, Katy Börner, Andreas Bueckle, Ying‐Hua Cheng, Pierre C. Dagher, Kenneth W. Dunn, Michael T. Eadon, Michael J. Ferkowicz, Bruce W. Herr, Katherine Kelly, Ricardo Melo Ferreira, Ellen M. Quardokus
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.