Abstract
Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.
Highlights
Diabetes is the leading cause of end-stage renal disease worldwide
We identified 2451 urinary proteins from 30 otherwise healthy youths with and without type 1 diabetes (Fig 2A)
Using a discovery-based proteomic analysis of urine samples from otherwise healthy youths with and without type 1 diabetes, we identified a urinary signature of 34 proteins dominated by lysosomal enzymes
Summary
Diabetes is the leading cause of end-stage renal disease worldwide. In the clinic, an early sign of diabetic kidney injury is microalbuminuria, which has traditionally been regarded as a defining point in the course of disease [1, 2]. Notable features of the diabetic kidney under the microscope include mesangial expansion, glomerular basement membrane thickening, and podocyte loss, which are often present long before the onset of microalbuminuria or decline in kidney function [10]. Building on this framework has been difficult, as kidney biopsies carry significant morbidity and are typically performed in cases of advanced or atypical diabetic kidney disease. Major gaps in knowledge continue to exist and present as barriers to improving care and delivering targeted treatments
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