RICERCA ITALIANA     

Causes, consequences, and therapeutic aspects of hyperhomocysteinemia in uremia and in diabetes.

Seconda Università degli Studi di Napoli

Abstract

Chronic Renal Failure (CRF), its end-stage, uremia, and diabetes mellitus, represent important causes of death in the general population. These diseases present high mortality rates (about 10 % per year in uremics), due to large extent to cardiovascular accidents (myocardial infarction, stroke, thrombosis, and in general to consequences of atherosclerosis). Lately, we have witnessed an effort from the scientific community to identify risk factors, implicated in the pathogenesis of the generalized atherosclerosis, typical of these diseases. In fact, traditional risk factors by themselves cannot be exhaustive in the understanding of the causes of atherosclerosis, and new risk factors, such as inflammation and hyperhomocysteinemia (hyper-tHcy) are at the moment under scrutiny.
An elevation in blood homocysteine (Hcy), a sulfur amino acid, is associated, even if the increase is mild or moderate, to an increase in cardiovascular risk. In addition, both in CRF and in diabetes with CRF, hyper-tHcy of moderate-severe grade is observed, which correlates with cardiovascular risk. Causes and consequences of hyper-tHcy, as well as the effects of hyper-tHcy therapy, performed with folate utilization, are still not well understood.
In our project, we propose to investigate several aspects of hyper-tHcy in CRF and diabetes, with the aim of clarifying the diverse implications of hyper-tHcy at the molecular level, on DNA and proteins, and at the metabolic level in the whole >>>

Principal Investigator

Natale Gaspare DE SANTO Seconda Università degli Studi di NAPOLI

Research Objectives

The objectives of the research projects coordinated by Prof. De Santo are basically focused on three aspects: 1) to clarify the mechanisms causing high levels of plasma Hcy, a known cardiovascular risk factor, in CRF, uremia and diabetes with CRF; 2) the consequences of hyper-tHcy in these diseases, in which a chronic increase in Hcy levels is observed; 3) to study the effects of folate therapy on this risk factor, and the effects of renal replacement therapy. The diseases under scrutiny display high morbidity and mortality, therefore a better understanding of the mechanisms leading to Hcy toxicity and of its metabolism are important in view of a future improvement in patient life expectancy.

Aims of Prof. De Santo's project will be: a) to evaluate the effects of protein homocysteinylation in cell colture models, and in mononuclear cells obtained from patients on hemodialysis; b) to demonstrate the hypothesis that protein carbamylation interferes with macromolecule homocysteinylation; c) to study the alterations in folate receptor expression in monocytes obtained from uremic patients on hemodialysis, before and after folate treatment, and their role in the pathogenesis of the alterations in sulfur amino acid metabolism.
Infact, protein homocysteinylation could be one of the principal mediators of Hcy toxic effects, thus contributing to determine structural and functional alterations at the molecular and cellular level. In addition, it is possible >>>

Timescale

24 months

National and international background

Chronic renal failure (CRF), its end-stage, termed uremia, and diabetes mellitus represent important causes of morbidity and mortality in the general population. It has been estimated that in the world about one million and a half people need replacement therapy, and therefore are dialyzed or are transplanted (and at least as many don't have access to therapy), and about 13 % is in pre-terminal chronic renal failure (with a glomerular filtration rate, GFR, lower than 59 ml/min). Diabetics amount to about 5 % of the population. Estimates, based on the increase in life expectancy, of pathological states such as obesity, and risk factors such as hypertension, predict that these numbers are destined to increase exponentially in the near future (1).
These diseases (CRF, uremia, and diabetes) are characterized by high morbidity and mortality (about 10 % per year in uremics, for example), which are mostly caused bt cardiovascular disease (therefore myocardial infarction, stroke, arterial and venous thrombosis, and in general consequences of atherosclerosis). Traditional risk factors cannot by themselves be exaustive in the understanding of the causes of atherosclerosis, and new risk factors, such as inflammation and hyper-tHcy are under scrutiny.
An elevation of plasma Hcy is associated to an increase in risk for cardiovascular accidents, that is myocardial infarction, stroke, arterial and venous thrombosis (2). Hcy is a sulfhydril amino acid, metabolized to >>>