Protein N-Glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease

作者：Dušan Veličković, John P. Shapiro, Samir V. Parikh, Brad H. Rovin, Robert D. Toto, Miguel Vazquez, Emilio D. Poggio, John F. O’Toole, John R. Sedor, Theodore Alexandrov, Sanjay Jain, Markus Bitzer, Jeffrey B. Hodgin, Marija Veličković, Kumar Sharma, Christopher Anderton, for the Kidney Precision Medicine Project · 发表于：Journal of the American Society of Nephrology · 年份：2024 · DOI：10.1681/asn.0000000000000393 · 被引用次数：19 · 研究领域：Glycosylation and Glycoproteins Research、Galectins and Cancer Biology、Lysosomal Storage Disorders Research

Key Points Multiomics performed on diabetic kidney disease biopsies revealed five N -glycan signatures of sclerotic glomeruli that significantly differed compared with healthy glomeruli. Integrative spatial glycomics, proteomics, and transcriptomics revealed protein N -glycosylation characteristic of sclerotic glomeruli in diabetic kidney disease. Background Diabetes is expected to directly affect renal glycosylation; yet to date, there has not been a comprehensive evaluation of alterations in N -glycan composition in the glomeruli of patients with diabetic kidney disease (DKD). Methods We used untargeted mass spectrometry imaging to identify N -glycan structures in healthy and sclerotic glomeruli in formalin-fixed paraffin-embedded sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation. Secondary analysis of single-nucleus RNA sequencing (snRNAseq) data were used to inform on transcript levels of glycosylation machinery in different cell types and states. Results We detected 120 N -glycans, and among them, we identified 12 of these protein post-translated modifications that were significantly increased in glomeruli. All glomeruli-specific N -glycans contained an N -acetyllactosamine epitope. Five N -glycan structures were highly discriminant between sclerotic and healthy glomeruli. Scl...