Membrane transport alterations in disease states

Thesis

The present thesis investigates cell membrane abnormalities in selected diseases. Membrane transport systems are studied in chronic renal failure (CRF), endstage diabetic nephropathy, renal transplantation and atherosclerotic vascular disease. The role of membrane cholesterol concentration in modulating transport activity is also explored.

Erythrocyte choline uptake is elevated in CRF and here it is shown that transporter activity returns to normal following a successful kidney transplant. Choline uptake recovers in parallel to the plasma creatinine changes. Plasma factors are suggested to play a role in transport activity in uraemia. The activity of the leucocyte sodium-hydrogen antiporter (Na/H) is shown to be normal in CRF with or without end-stage diabetic nephropathy. Erythrocyte lactate transport was investigated at 37°C for the first time. Kinetic parameters of transport were characterized. Lactate uptake in erythrocytes is mediated mainly via the monocarboxylate carrier. No lactate transport alterations are present in uraemic patients when compared with normal subjects.

The possible influence of membrane cholesterol on the activity of transporters in disease was approached in two ways. First, cell cholesterol content was modulated in vitro employing liposomes. With this approach, lymphoblast Na/H antiporter activity is inhibited by cholesterol-enrichment while activation is seen with cholesterol-depletion. Erythrocyte choline uptake was insensitive to cholesterol modulation. It is suggested that membrane cholesterol content is unlikely to contribute to the membrane transport abnormalities in the uraemic syndrome. In erythrocytes liposome depletion of cholesterol reduced Na/Li countertransport activity. In vivo treatment with the HMG CoA reductase inhibitor simvastatin, which reduces plasma cholesterol levels, was employed to look at Na/Li countertransport activity in patients with atherosclerotic vascular disease. Although simvastatin reduces mean cholesterol by about 30%, there was no change in erythrocyte mean cholesterol content. Erythrocyte Na/Li countertransport was unaffected by simvastatin treatment. Accordingly an in vivo relationship between membrane cholesterol and Na/Li countertransport activity could not be tested in this study.

The present results emphasize the selective nature of alterations in membrane composition and function in various disease states.

Authors: de Figueiredo, C

• Peer review status: Peer reviewed
• DOI: 10.5287/ora-xkro7ana8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford