The Anti-Proteinuric Effects of Unsaturated Fatty Acid Diets in Healthy Rats

Proteinuria is the hallmark of impaired glomerular permselectivity and is associated with a poor prognosis in renal disease. It is widely acknowledged that a fall in urine protein excretion may indicate an improvement in renal function or retardation of disease progression. The finding that diets rich in polyunsaturated fatty acids (PUFA), reduced urine albumin excretion in two healthy strains of rat (Lewis and DA) with differing susceptibilities to glomerular disease, was therefore deemed worthy of further investigation. Each successive study in this thesis is an attempt to unravel the mechanism behind the apparent anti-proteinuric actions of PUFA diets. However, establishing a relationship between PUFA diets and albumin excretion is complicated by not only the many and varied functions of PUFAs which include eicosanoid biosynthesis, cell membrane structure and function and lipid metabolism but also the various factors which control the filtration of albumin such as glomerular capillary wall structure and charge, glomerular haemodynamics and the physico-chemical characteristics of the filtered molecule. As precursors of prostaglandins and thromboxane, polyunsaturated fatty acids can regulate glomerular blood flow and pressure and modulate the activity of the renin- angiotensin system but ultimately, the observed fall in albumin excretion rate in Lewis and DA rats could neither be attributed to changes in glomerular or circulating levels of prostaglandins, thromboxane or renin levels in the PUFA diet groups. That PUFA diets might effect changes in the intrinsic permeability properties of the glomerular capillary wall in such a way as to reduce the filtration of albumin was explored by assessing the magnitude of the negative charge on the glomerular capillary wall (glomerular polyanion). Lewis rat glomeruli sequestered significantly less of a radiolabelled cationic protein probe than DA rat glomeruli and this was taken as confirmation of a diminished glomerular polyanion in Lewis rats relative to DA rats but overall, PUFA diets had little effect on glomerular capillary wall charge. The binding of fatty acids to serum albumin can alter the electrical charge of the albumin molecule and it was shown that the isoelectric point of Lewis rat serum albumin was reduced in all the experimental PUFA diet groups compared to that from rats fed a standard laboratory diet. Structural modification of the serum albumin molecule, induced by the binding of unsaturated fatty acids, may have further increased its anionic charge and thereby reduced its filtration across the glomerular capillary wall. The PUFA diet-induced fall in albumin excretion rate in healthy Lewis and DA rats prompted a study to investigate the capacity of evening primrose oil diet to prevent an anticipated rise in albumin excretion rate in diabetic Lewis rats. Although it reduced both total protein and albumin excretion in Lewis rats during the non-diabetic phase of the study, evening primrose oil diet did not prevent a rise in albumin excretion rate in diabetic Lewis rats. It is unlikely that the anti-proteinuric effects of PUFA diets in healthy Lewis and DA rats were mediated by either changes in glomerular prostanoid or renin levels or the intensity of the glomerular polyanion and is more likely to be related to a change in the isoelectric point (pi) of the albumin molecule as a result of binding fatty acids. The failure to demonstrate a fall in albumin excretion rate in diabetic Lewis rats fed evening primrose oil diet could be due to competition between glucose and fatty acid molecules for binding sites on the albumin molecule