Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.
Diabetes, 2022/12/01;71(12):2664-2676.
Liu J[1, 2], Nair V[1], Zhao YY[3], Chang DY[3], Limonte C[4], Bansal N[4], Fermin D[1], Eichinger F[1], Tanner EC[1], Bellovich KA[5], Steigerwalt S[6], Bhat Z[7], Hawkins JJ[1], Subramanian L[1], Rosas SE[8], Sedor JR[9], Vasquez MA[10], Waikar SS[11], Bitzer M[1], Pennathur S[1], Brosius FC[1, 12], De Boer I[4], Chen M[3], Kretzler M[1, 13], Ju W[1, 13], Kidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group, Kidney Precision Medicine Project and Michigan Translational Core C-PROBE Investigator Group
Affiliations
PMID: 36331122DOI: 10.2337/db22-0169
Impact factor: 9.337
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.
MeSH terms
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
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