Shift of high-density lipoprotein size distribution toward large particles in patients with proteinuria

Soto-Miranda, Ernesto; Carreón‐Torres, Elizabeth; Lorenzo, Karina; Bazán-Salinas, Berenice; García-Sánchez, Cynthia; Franco, Martha; Posadas‐Romero, Carlos; Fragoso, J.M.; López-Olmos, Victoria; Madero, Magdalena; Rodríguez-Pérez, José Manuel; Vargas‐Alarcón, Gilberto; Pérez-Méndez, Óscar

doi:10.1016/j.cca.2012.09.028

Cited by 14 publications

(23 citation statements)

References 33 publications

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“…43 Furthermore, a study of normoalbuminuric patients with type 1 diabetes and normal glomerular function reported a correlation between lower levels of total HDL-C and smaller HDL 3 -C with albuminuria, but not larger HDL 2 -C. 44 Similarly, HDL size distribution has shifted toward large particles in patients with proteinuria. 45 However, further work is required to analyze cubilin expression in these patient populations and determine whether a causal link exists between any changes in cubilin expression and altered HDL levels. Demonstrating such a link would emphasize the need to upregulate the renal cubilinmediated salvage pathway to prevent CVD in these patient populations.…”

Section: Discussionmentioning

confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL 3 particles (density.1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL 2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.

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Section: Discussionmentioning

confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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“…Indeed, patients with moderate glomerular impairment have increased fractional catabolic rate of ApoA-I and small HDL3 (71,72). Patients with proteinuria but without diabetes show a shift in HDL size distribution towards large particles consistent with selective renal loss of small HDL particles (103). Even in the absence of reduced GFR, proteinuria causes lipid abnormalities including reduced levels of HDL-C (104–108).…”

Section: Introductionmentioning

confidence: 99%

Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein

Kon¹,

Yang²,

Fazio³

2015

Archives of Medical Research

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Although reducing low-density lipoprotein-cholesterol (LDL-C) levels with lipid-lowering agents (statins) decreases cardiovascular disease (CVD) risk, a substantial residual risk (up to 70% of baseline) remains after treatment in most patient populations. High-density lipoprotein (HDL) is a potential contributor to residual risk, and low HDL-cholesterol (HDL-C) is an established risk factor for CVD. However, in contrast to conventional lipid-lowering therapies, recent studies show that pharmacologic increases in HDL-C levels do not bring about clinical benefits. These observations have given rise to the concept of dysfunctional HDL where increases in serum HDL-C may not be beneficial because HDL loss of function is not corrected by or even intensified by the therapy. Chronic kidney disease (CKD) increases CVD risk, and patients whose CKD progresses to end-stage renal disease (ESRD) requiring dialysis are at the highest CVD risk of any patient type studied. The ESRD population is also unique in its lack of significant benefit from standard lipid-lowering interventions. Recent studies indicate that HDL-C levels do not predict CVD in the CKD population. Moreover, CKD profoundly alters metabolism and composition of HDL particles and impairs their protective effects on functions such as cellular cholesterol efflux, endothelial protection, and control of inflammation and oxidation. Thus, CKD-induced perturbations in HDL may contribute to the excess CVD in CKD patients. Understanding the mechanisms of vascular protection in renal disease can present new therapeutic targets for intervention in this population.

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“…A previous report showed that patients with type 1 diabetes within the higher values of the normal range of albuminuria had lower plasma HDL3-cholesterol levels than patients within the lower values of albuminuria (<11 mg/dL) [27]. Additionally, in a rabbit model with partial (75 %) nephrectomy, we previously reported an increase of HDL2b and a decrease of HDL3a [7], as well as a shift of HDL size distribution toward large HDL subclasses in patients with proteinuria [10]. Since HDL have a molecular mass that ranges from 200 to 400 kDa [28], these studies suggested that there was a preferential renal elimination of small HDL particles associated with proteinuria.…”

Section: Discussionmentioning

confidence: 90%

“…In the context of an impaired renal function, HDL-cholesterol and apo A-I in plasma are significantly modified [8,9] and patients in such conditions have an increased risk of coronary heart disease (CHD). Moreover, previous evidence from our group has suggested that the kidney easily eliminates small HDL particles, while large HDL remain in the plasma of patients with proteinuria [10]. Accordingly, rabbits with partial (75 %) nephrectomy have an increased proportion of large HDL2b and decreased levels of HDL3a [7].…”

Section: Introductionmentioning

confidence: 94%

Increased HDL Size and Enhanced Apo A‐I Catabolic Rates Are Associated With Doxorubicin‐Induced Proteinuria in New Zealand White Rabbits

López-Olmos

Carreón‐Torres

Luna-Luna

et al. 2016

Lipids

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The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

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Shift of high-density lipoprotein size distribution toward large particles in patients with proteinuria

Cited by 14 publications

References 33 publications

Cubilin Maintains Blood Levels of HDL and Albumin

Cubilin Maintains Blood Levels of HDL and Albumin

Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein

Increased HDL Size and Enhanced Apo A‐I Catabolic Rates Are Associated With Doxorubicin‐Induced Proteinuria in New Zealand White Rabbits

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