Submitted to: Journal of the American Society of Nephrology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/25/2005
Publication Date: 5/16/2005
Citation: Shearer, G.C., Newman, J.W., Hammock, B.D., Kaysen, G.A. The graded effects of proteinuria on HDL structure in nephrotic rats. Journal of the American Society of Nephrology. 16: 1309-1319, 2005. Interpretive Summary: Inflammation of the kidney is associated with protein loss in the urine and a reduced ability for the body to clear triglyceride-rich lipid particles from the blood stream. In healthy animals, a protein called apolipoprotein E, or simply apoE, is transferred from protein rich high density lipoproteins (HDL) to the triglyceride-rich particles and HDL apoE known to be lost under conditions of massive urinary protein loss. However, even minor amounts of urinary protein are associated with increased cardiovascular risk and some of this risk may be associated with altered HDL structure. Using a rodent model of renal inflammation, a set of animals was produced with minimal or intermediate levels of kidney injury-associated urinary protein excretion. We found that while apoE levels were not affected at minimal levels of protein loss, apoA-IV was reduced while apoA-II, apoC-II, and apoC-III increased showing that HDL is structurally altered when levels of urinary albumin excretion are insufficient to change serum albumin levels. The observed changes in HDL structure associated with minimal albuminuria would mechanistically favor increased cardiovascular risk, suggesting that these changes themselves may indicate novel risk factors to the processes associated with increased cardiovascular disease in nephrotic subjects.
Technical 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.