Graded Effects of Proteinuria on HDL Structure in Nephrotic Rats

Abstract

Nephrotic syndrome is characterized by increased triglycerides resulting from decreased clearance of VLDL and chylomicrons. These triglyceride-rich lipoproteins are structurally altered by interaction with HDL derived from animals with proteinuria and not as a consequence of hypoalbuminemia. HDL isolated from rats with massive proteinuria is depleted in apolipoprotein E (apoE). It is unknown at what threshold of urinary albumin loss HDL structure is altered, and it is unknown what effects proteinuria has on apolipoproteins other than apoE. Two models of albuminuria were used in Sprague-Dawley rats: Adriamycin and passive Heymann nephritis (HN). The adriamycin group was divided into minimal albumin excretion (MAE) and intermediate albumin excretion (MAE, 1 to 40; intermediate albumin excretion, 60 to 210 mg/d per 100 g body wt). Urinary albumin excretion exceeded 300 mg/d per 100 g body wt in the HN rats. HDL apolipoprotein composition was analyzed with SDS-PAGE densitometry and liquid chromatography-time of flight mass spectrometer mass spectrometry. HDL apoA-IV content relative to apoA-I was reduced at all levels of albuminuria (P < 0.0001). ApoE was not reduced in MAE but was significantly reduced in IAE (72%; P < 0.001). By contrast, apoA-II and apoC-III were each significantly increased with increasing UAE. ApoA-IV and apoE were decreased to approximately 10% of control in HDL isolated from rats with HN, whereas apoA-II, apoC-II, and apoC-III were each significantly increased relative to apoA-I. HDL is structurally altered by levels of albuminuria that are insufficient to change serum albumin levels and is progressively altered as albuminuria increases.J H yperlipidemia in the nephrotic syndrome is a result of increased synthesis (1,2) and decreased catabolism (1,3,4). VLDL levels are increased predominantly as a consequence of decreased catabolism both in rats with the nephrotic syndrome (4) and in humans (5). VLDL from nephrotic rat plasma does not bind normally to vascular endothelial cells, a consequence of reduced apolipoprotein E (apoE) content. Nascent VLDL functions normally when secreted by nephrotic livers but acquires a structural and functional defect through interaction with nephrotic HDL after VLDL secretion (6). The alteration in HDL structure and function results directly from proteinuria (3,6) and not from hypoalbuminemia.We have shown that defective clearance of VLDL in nephrotic rats requires interaction with HDL from proteinuric animals and that hypoalbuminemia does not deleteriously affect HDL structure. Although we have analyzed the effect of nephrotic range albuminuria on HDL structure, the effects of lesser amounts of albuminuria have not been well examined. Even small amounts of albuminuria are associated with increased relative risk for vascular disease in both diabetes (7,8) and hypertension (9,10). This association is generally believed to reflect underlying endothelial dysfunction in patients with microalbuminuria, causing both the renal albumin leak and the association with vasc...

Risk factors in V‐shaped risk associations with all‐cause mortality in type 2 diabetes—The Hong Kong Diabetes Registry

“…In support of these 'paradoxical' findings, in a 3-year clinical trial comparing the effects of Enalapril and Nifedipine in hypertensive type 2 diabetic patients, high HDL-C was an independent predictor of declining GFR [28]. There are clinical and experimental evidence suggesting alterations in structure and function of HDL-C particles in the presence of albuminuria and renal dysfunction [29,30]. These include decreased clearance of TG, increased transfer of TG to HDL-C with increased catabolism, leading to low apo-AI levels.…”

The Experimental Model of the Autoimmune Glomerulonephritis Induced by the Chronic Graft versus Host Reaction

“…It has been found experimentally that kidney disease combines not only with changes serum lipid levels, but also with a variety of disorders of lipid metabolism in tissues. In clinical and experimental works it has been evidenced that nephrotic syndrome is accompanied by significant changes in activity of some enzymes involved in cholesterol metabolism (such as HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase, lecithin-cholesterol acyltransferase and other), by decreased expression of LDL receptors on membranes of hepatocytes, by decline of apolipoprotein E, and by impaired reverse cell cholesterol transport (Subbaiah & Rodby, 1994;Deighan et al, 2000;Vaziri & Liang, 2002;Shearer et al, 2005;Vaziri et al, 2011). Undoubtedly, these data are very important for deep understanding of the pathogenesis of hypercholesterolemia in nephrotic syndrome, but they do not clarify the question what are mechanisms linking kidney disease and changes in lipid metabolism.…”

Proteinuria increases oxylipid concentrations in VLDL and HDL but not LDL particles in the rat

“…The lipid and protein content of each lipoprotein fraction was measured, and the remaining lipoprotein was stored under nitrogen at 220jC for oxylipid analysis. The pseudo-quantification of fractional apoE and apoA-I was accomplished by HPLC electrospray ionization time-of-flight (HPLC/ESI-TOF) mass spectral detection as previously described (8). Oxylipids were determined in a 250 ml aliquot of each density fraction.…”

“…Proteinuria has been reported to shift the balance of lipoprotein apolipoproteins, with the apoA-I to apoE ratio being a good reporter of dysfunctional lipoproteins in the nephrotic syndrome (8). Therefore, the influence of proteinuria on HDL apoA-I and apoE was assessed by HPLC/ESI-TOF MS to further characterize the experimental animals.…”

“…The prevalent hypothesis linking microalbuminuria to vascular disease is that proteinuria reports endothelial injury (4)(5)(6)(7). However, even small amounts of urinary protein loss in the rat alter plasma lipid levels and the apolipoprotein content of lipoproteins (8). In addition to their role in mediating forward and reverse lipid transport, lipoproteins also influence inflammation, vascular tension (9), vascular permeability, and oxidative stress (10).…”