Early urinary biomarkers of diabetic nephropathy in type 1 diabetes mellitus show involvement of kallikrein-kinin system

Abstract

BackgroundAdditional urinary biomarkers for diabetic nephropathy (DN) are needed, providing early and reliable diagnosis and new insights into its mechanisms. Rigorous selection criteria and homogeneous study population may improve reproducibility of the proteomic approach.MethodsLong-term type 1 diabetes patients without metabolic comorbidities were included, 11 with sustained microalbuminuria (MA) and 14 without MA (nMA). Morning urine proteins were precipitated and resolved by 2D electrophoresis. Principal component analysis (PCA) and Projection to latent structures discriminatory analysis (PLS-DA) were adopted to assess general data validity, to pick protein fractions for identification with mass spectrometry (MS), and to test predictive value of the resulting model.ResultsProteins (n = 113) detected in more than 90% patients were considered representative. Unsupervised PCA showed excellent natural data clustering without outliers. Protein spots reaching Variable Importance in Projection score above 1 in PLS (n = 42) were subjected to MS, yielding 33 positive identifications. The PLS model rebuilt with these proteins achieved accurate classification of all patients (R2X = 0.553, R2Y = 0.953, Q2 = 0.947). Thus, multiple earlier recognized biomarkers of DN were confirmed and several putative new biomarkers suggested. Among them, the highest significance was met in kininogen-1. Its activation products detected in nMA patients exceeded by an order of magnitude the amount found in MA patients.ConclusionsReducing metabolic complexity of the diseased and control groups by meticulous patients’ selection allows to focus the biomarker search in DN. Suggested new biomarkers, particularly kininogen fragments, exhibit the highest degree of correlation with MA and substantiate validation in larger and more varied cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-017-0519-4) contains supplementary material, which is available to authorized users.

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

“…Irregularities in plasma KKS homeostasis have been demonstrated in individuals with type 1 diabetes and diabetic nephropathy [8][9][10], but the reason behind the decline in plasma kallikrein activity in our study is unknown. As plasma kallikrein circulates in complex with HMW-kininogen (280 kDa), it is unlikely to be filtered out when bound to its cofactor.…”

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

“…Activated DPP-4 interacts with integrin b1 and induces its phosphorylation. Activated DPP-4 phosphorylated integrin b1 complex triggers transforming growth factor-β (TGF-β) receptor dimerization and activation of vascular endothelial growth factor receptor Type 1 [36]. Hyperglycemia, free oxygen radicals, and proteinuria causes activation of NF-jB is within the diabetic kidney [37].…”

The role of mass spectrometry in studies of glycation processes and diabetes management

“…Moreover, another advantage of using urine, instead of blood, is its easy and non‐invasive collection that allows repeated sampling for disease monitoring. In the last years, several studies have been performed, in urines, aiming to identify biomarkers that can detect early stages of DN and progressive kidney function decline in diabetic patients, as well as biomarkers that can allow for a non‐invasive diagnosis of kidney disease (Chang et al ., ; Chu et al ., ; Manwaring et al ., ; Merchant et al ., ; Lewandowicz et al ., ; Siwy et al ., ; Vitova et al ., ; Wheelock et al ., ).…”

“…Moreover, another advantage of using urine, instead of blood, is its easy and non-invasive collection that allows repeated sampling for disease monitoring. In the last years, several studies have been performed, in urines, aiming to identify biomarkers that can detect early stages of DN and progressive kidney function decline in diabetic patients, as well as biomarkers that can allow for a non-invasive diagnosis of kidney disease (Chang et al, 2017;Chu et al, 2013;Manwaring et al, 2013;Merchant et al, 2013;Lewandowicz et al, 2015;Siwy et al, 2017;Vitova et al, 2017;Wheelock et al, 2017). Siwy et al (2017) by using CE-MS aimed to verify if urinary proteome analysis holds information on disease etiology and allows to discriminate among seven different types of CKD that in the current clinical practice are defined by pathological assessment of renal biopsies.…”

“…Authors suggest that plasmatic bradykinin and related peptides may have a possible reno-protective role. Despite plasma measures may not mirror concentrations in urines or within kidney tissue, it is interesting to observe that Vitova et al (2017) found that a diminished urinary excretion of kininogen-1 heavy chain was the most significant predictor for MA assignment, as if lower amounts can be considered responsible of the development and progression of DN disease. Contrary to these authors that associated low levels of kininogen and bradykinin with renal disease, Merchant et al (2013) found that plasma kininogen and its fragments are biomarkers of progressive renal decline in type 1 diabetes.…”