Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.
washington; spokane; Humans; Angiopoietin-1; Receptor, TIE-2; Diabetic Nephropathies; Cohort Studies; Endothelial Cells; Angiopoietin-2; Angiopoietins; Signal Transduction; Biomarkers; Kidney Failure, Chronic; Disease Progression; Diabetes Mellitus
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.
Kidney & Diabetes
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; Kidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group; and Tuttle, Katherine, "Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease." (2022). Articles, Abstracts, and Reports. 6743.