Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease
Authors: Liu Jiahao , Nair Viji , Zhao Yi-yang , Chang Dong-yuan , Limonte Christine , Bansal Nisha , Fermin Damian , Eichinger Felix , Tanner Emily C. , Bellovich Keith A. , Steigerwalt Susan , Bhat Zeenat , Hawkins Jennifer J. , Subramanian Lalita , Rosas Sylvia E. , Sedor John R. , Vasquez Miguel A. , Waikar Sushrut S. , Bitzer Markus , Pennathur Subramaniam , Brosius Frank C. , De Boer Ian , Chen Min , Kretzler Matthias , Ju Wenjun ,   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, Knight Richard , Lecker Stewart H. , Stillman Isaac , Bogen Steve , Amodu Afolarin A. , Ilori Titlayo , Maikhor Shana , Schmidt Insa , Beck Laurence H. , Henderson Joel M. , Onul Ingrid , Verma Ashish , Waikar Sushrut , McMahon Gearoid M. , Valerius M. Todd , Waikar Sushrut , Weins Astrid , Colona Mia R. , Greka Anna , Hacohen Nir , Hoover Paul J. , Marshall Jamie L. , Aulisio Mark , Chen Yijiang M. , Janowczyk Andrew , Jayapandian Catherine , Viswanathan Vidya S. , Bush William S. , Crawford Dana C. , Madabhushi Anant , Bush Lakeshia , Cooperman Leslie , Gonzalez-Vicente Agustin , Herlitz Leal , Jolly Stacey , Nguyen Jane , O’toole John , Palmer Ellen , Poggio Emilio , Sedor John , Sendrey Dianna , Spates-Harden Kassandra , Taliercio Jonathan , Bjornstad Petter M. , Pyle Laura , Vinovskis Carissa , Appelbaum Paul , Barasch Jonathan M. , Bomback Andrew S. , Canetta Pietro A. , D’Agati Vivette D. , Kiryluk Krzysztof , Kudose Satoru , Mehl Karla , Shang Ning , Balderes Olivia , Bansal Shweta , Alexandrov Theodore , Rennke Helmut , El-Achkar Tarek M. , Barwinska Daria , Bledsoe Sharon , Borner Katy , Bueckle Andreas , Cheng Yinghua , Dagher Pierre C. , Dunn Kenneth W. , Eadon Michael T. , Ferkowicz Michael J. , Herr Bruce W. , Kelly Katherine J. , Melo Ferreira Ricardo , Quardokus Ellen M. , Record Elizabeth , Rivera Marcelino , Su Jing , Sutton Timothy A. , Williams James C. , Winfree Seth , Menez Steven , Parikh Chirag R. , Rosenberg Avi , Corona-Villalobos Celia P. , Wen Yumeng , Johansen Camille , Rosas Sylvia E. , Roy Neil , Sun Jennifer , Williams Mark , Azeloglu Evren U. , Hansen Jens , He Cijang , Iyengar Ravi , Xiong Yuguang , Prasad Pottumarthi , Srivastava Anand , Madhavan Sethu M. , Parikh Samir , Rovin Brad , Shapiro John P. , Anderton Christopher R. , Lukowski Jessica , Pasa-Tolic Ljiljana , Velickovic Dusan , Oliver George (Holt) , Ardayfio Joseph , Bebiak Jack , Brown Keith , Campbell Taneisha , Campbell Catherine E. , Hayashi Lynda , Jefferson Nichole , Roberts Glenda V. , Saul John , Shpigel Anna , Stutzke Christy , Koewler Robert , Pinkeney Roy , Sealfon Rachel , Troyanskaya Olga , Wong Aaron , Tuttle Katherine R. , Pollack Ari , Goltsev Yury , Lucarelli Nicholas , Sarder Pinaki , Lake Blue B. , Zhang Kun , Boada Patrick , Laszik Zoltan G. , Nolan Garry , Anjani Kavya , Sarwal Minnie , Mukatash Tariq , Sigdel Tara , Alloway Rita R. , Burg Ashley R. , Lee Paul J. , Rike Adele , Shi Tiffany , Woodle E. Steve , Balis Ulysses G.J. , Blanc Victoria M. , Conser Ninive C. , Eddy Sean , Frey Renee , He Yougqun , Hodgin Jeffrey B. , Kretzler Matthias , Lienczewski Chrysta , Luo Jinghui , Mariani Laura H. , Menon Rajasree , Otto Edgar , Schaub Jennifer , Steck Becky , Elder Michele M. , Gilliam Matthew , Hall Daniel E. , Murugan Raghavan , Palevsky Paul M. , Randhawa Parmjeet , Rosengart Matthew , Tublin Mitchell , Vita Tina , Kellum John A. , Winters James , Alpers Charles E. , Berglund Ashley , Blank Kristina N. , Carson Jonas , Daniel Stephen , De Boer Ian H. , Dighe Ashveena L. , Dowd Frederick , Grewenow Stephanie M. , Himmelfarb Jonathan , Hoofnagle Andrew N. , Limonte Christine , McClelland Robyn L. , Mooney Sean D. , Rezaei Kasra , Shankland Stuart , Snyder Jamie , Wang Ruikang , Wilcox Adam , Williams Kayleen , Park Christopher , Bansal Shweta , Montellano Richard , Pamreddy Annapurna , Sharma Kumar , Venkatachalam Manjeri , Ye Hongping , Zhang Guanshi , Hedayati S. Susan , Kermani Asra , Lee Simon C. , Lu Christopher Y. , Miller R. Tyler , Moe Orson W. , Patel Jiten , Pillai Anil , Sambandam Kamalanathan , Torrealba Jose , Toto Robert D. , Vazquez Miguel , Wang Nancy , Wen Natasha , Zhang Dianbo , Park Harold , Caprioli Richard M. , Patterson Nathan , Sharman Kavya , Spraggins Jeffrey M. , Van de Plas Raf , Basta Jeanine , Diettman Sabine M. , Gaut Joseph P. , Jain Sanjay , Rauchman Michael I. , Vijayan Anitha , Cantley Lloyd G. , Kakade Vijaykumar R. , Moledina Dennis , Shaw Melissa M. , Ugwuowo Ugochukwu , Wilson Francis P. , Arora Tanima , Bitzer Markus , Brosius Frank C. , Gadegbeku Crystal , Gipson Debbie , Hawkins Jennifer , Kretzler Matthias , Lienczewski Chrysta , Pennathur Subramaniam , Troost Jonathan , Gadegbeku Crystal , Bellovich Keith , Bhat Zeenat , Massengill Susan , Perumal Kalyani 
Published: November 2022

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.