Characterization of urine proteome pattern changes associated with early diabetic nephropathy: a proteomic approach

by Hülya Kara née Karaköse
Doctoral thesis
Date of Examination:2024-07-02
Date of issue:2024-04-19
Advisor:Prof. Dr. Hassan Dihazi
Referee:Prof. Dr. Hassan Dihazi
Referee:PD Dr. Moritz Thomas Schnelle
Referee:Prof. Dr. Dr. Philipp Kauffmann
Persistent Address: http://dx.doi.org/10.53846/goediss-10453

 

 

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Abstract

English

Type 2 diabetes mellitus has become the most common cause of kidney failure in Europe and the United States. In Germany, 8.7 million people live with type 2 diabetes, although an estimated two million more affected people have not yet been diagnosed. Approximately 10–50% of all type 2 diabetes patients develop kidney involvement after a disease duration of 15–30 years. Long-term diabetes often leads to micro- and macrovascular impairment, leading to clinical complications in various organs such as retinopathy, cardiomyopathy, and nephropathy. Diabetic nephropathy (DN) is characterized by excessive extracellular matrix accumulation with thickening of glomerular and tubular basement membranes and an increased amount of mesangial matrix, ultimately leading to glomerulosclerosis and tubulo-interstitial fibrosis. Systemic hypertension and hyperglycemia promote the development of severe glomerulosclerosis, which is manifested by a decrease in the glomerular filtration rate (GFR) and macroalbuminuria (albumin excretion > 300 mg/24 h). The overall aim of this work was to adapt a urine protein preparation protocol and combine this with mass spectrometric analysis and label-free quantification to identify proteins that are differentially excreted into urine in the early stages of diabetic nephropathy. These could potentially serve as early markers of kidney lesions in diabetics. This means that earlier treatment can slow or even stop the progression of the disease. In this proteomic approach, diabetics with micro- and macroalbuminuria were compared with diabetics without nephropathy and patients with proteinuria but without diabetes. We have shown that a significant degree of irreversible kidney damage can occur before the onset of micro- and macroalbuminuria, as many key proteins involved in tubular epithelial cell damage and inflammation are increased. As the disease (DN) progresses, protein groups increase due to tubular epithelial cell damage (E-Cadherin p=0.001, NGAL, Cubilin), endothelial cell damage (Angiotensinogen p=0.04, Vascular cell adhesion protein 1 p=0.002, cell adhesion molecules, VWA7 p=0.002), and glomerular barrier damage (Serotransferrin, Ceruloplasmin). Potential biomarkers such as E-cadherin and other proteins showed promising results, were associated with microalbuminuria, and demonstrated robust study results for the diagnosis of early-stage diabetic nephropathy. Our research has shown that these proteins have the potential to be used as a prediagnostic marker for diabetic patients at risk of kidney disease. For a marker or markers to be translated into medical care, rigorous testing in larger cohorts is required to validate reliability, repeatability, sensitivity, and specificity. Many of the discovered marker candidates still need to be validated.
Keywords: Diabetes Mellitus; Diabetic Nephropathy; Diabetic Kidney Disease; Albuminuria; Kidney; E-Cadherin; Proteomics
Schlagwörter: Diabetic nephropathy; Proteinuria; Diabetic kidney disease
 
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