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. 2016 Jun;241(11):1186-94.
doi: 10.1177/1535370216629007. Epub 2016 Feb 3.

Discovery and verification of urinary peptides in type 2 diabetes mellitus with kidney injury

Guangzhen Fu  1 , Ye Du  2 , Lina Chu  1 , Man Zhang  3
Affiliations

Discovery and verification of urinary peptides in type 2 diabetes mellitus with kidney injury

Guangzhen Fu et al. Exp Biol Med (Maywood). 2016 Jun.

Abstract

Varying degrees of renal injury could lead to different changes in urinary protein composition. We want to find urinary candidate peptide biomarkers in type 2 diabetic patients with different extents of kidney injury. Two sets of patients were recruited. Discovery set: weak cationic-exchange magnetic beads coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to profile the low-molecular weight peptidome in urine samples from type 2 diabetes patients with normoalbuminura and microalbuminuria. The differently expressed urinary peptides were screened by ClinProTools2.1 bioinformatics software and identified through nano-liquid chromatography-tandem mass spectrometry. Verification set: the above screened urinary peptides were validated by use matrix-assisted laser desorption ionization time-of-flight mass spectrometry on another group of type 2 diabetes patients with different extents use of kidney injury. In the screening and identification stages, seven urinary peptides were selected as the most promising biomarker candidates, and they were identified as fragments of vitronectin precursor, isoform 1 of fibrinogen alpha chain precursor, prothrombin precursor and inter-alpha-trypsin inhibitor heavy chain H4. The diagnostic efficacy of these urinary peptides was evaluated by area under the receiver operating characteristic curve, and they were 0.767, 0.768, 0.868, 0.910, 0.860, 0.843, and 0.865, respectively. In the verification stage, m/z 1743.9, 2154, 2175.5, and 2184.9 were decreased as albumin-to-creatinine (Alb/Cre) increased and m/z 2231.1, 2430.8, and 2756.1 were elevated as Alb/Cre rose. These small molecule peptides are related to type 2 diabetes kidney damage, and they may play an important role in monitoring type 2 diabetes.

Keywords: Urinary peptides; diabetes nephropathy; magnetic bead processing; matrix-assisted laser desorption ionization time-of-flight mass spectrometry; type 2 diabetes mellitus.

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Figures

Figure 1
Figure 1
Typical urinary sample mass spectrum from MALDI-TOF MS after purified by weak cation exchange magnetic beads. (a) From one sample of type 2 diabetic patients with normoalbuminuria. (b) From one sample of type 2 diabetic patients with microalbuminuria. (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
The features of the seven selected peaks in two groups of type 2 diabetic patients. (a) The distribution of average peak area from two groups. (b) The average values of three up-regulated peaks in two groups (left and right) and their distribution in all samples (middle). (c) The average value of four decreased peaks in two groups (left and right) and their distribution in all samples (middle). (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
The features of the seven selected peaks in two groups of type 2 diabetic patients. (a) The distribution of average peak area from two groups. (b) The average values of three up-regulated peaks in two groups (left and right) and their distribution in all samples (middle). (c) The average value of four decreased peaks in two groups (left and right) and their distribution in all samples (middle). (A color version of this figure is available in the online journal.)
Figure 3
Figure 3
Receiver operator characteristics (ROC) curves generated with the m/z 1743.9, 2154, 2175.5, 2184.9, and 2231.1, 2430.8, 2756.1 used to distinguish type 2 diabetic patients with microalbuminuria from type 2 diabetic patients with normoalbuminuria. The areas under the curve (AUC) were 0.767, 0.768, 0.868, 0.910, 0.860, 0.843, and 0.865 for the above mentioned peaks, respectively
Figure 4
Figure 4
The changing trend of the detected peaks screened from discovery set with the UAE in verification set. (a) The four down-regulated peaks were decline with UAE in type 2 diabetic patients with different extent of albumin-to-creatinine ratio. (b) The three up-regulated peaks were increased with UAE in type 2 diabetic patients with different extents of albumin-to-creatinine ratio. (A color version of this figure is available in the online journal.)
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