elastin and Diabetic-Nephropathies

During the past few years, proteomics has been extensively applied to various fields of medicine including nephrology. Current applications of renal and urinary proteomics are to better understand renal physiology, to explore the complexity of disease mechanisms, and to identify novel biomarkers and new therapeutic targets. This review provides some examples and perspectives of how proteomics can be applied to nephrology and how experimental data can be linked to physiology, functional significance and clinical applications. In some instances, proteomic analysis can be utilized to generate a new hypothesis from a set of candidates that are obtained from expression studies. The new hypothesis can then be addressed rapidly by conventional molecular biology methods, as demonstrated by identification of an altered renal elastin-elastase system in diabetic nephropathy and alterations in the renal kallikrein-kallistatin pathway in hypoxia-induced hypertension. The strengths and limitations of proteomics in renal research are summarized. Optimization of analytical protocols is required to overcome current limitations. Applications of proteomics to nephrology will then be more fruitful and successful.

Topics: Animals; Biomarkers; Carrier Proteins; Diabetic Nephropathies; Elastin; Gene Expression Regulation; Graft Rejection; Humans; Hypertension; Hypoxia; Kallikreins; Kidney; Kidney Transplantation; Models, Biological; Pancreatic Elastase; Proteomics; Serpins; Urine

Topics: Actin Cytoskeleton; Actins; Animals; Capillaries; Carrier Proteins; Cell Adhesion; Collagen; Diabetic Nephropathies; Elasticity; Elastin; Endothelium, Vascular; Fibrillins; Glomerular Mesangium; Glutathione; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Latent TGF-beta Binding Proteins; Mammals; Membrane Glycoproteins; Mice; Microfilament Proteins; Permeability; Rats; Transforming Growth Factor beta

Diabetes now accounts for >40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n = 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n = 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.

Topics: Animals; Diabetic Nephropathies; Elastin; Kidney; Mice; Mice, Transgenic; Pancreatic Elastase; Protein Biosynthesis; Proteomics