Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease

Abstract

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.

Keywords: atherosclerosis; cardiovascular disease; cholesterol; endothelins; triglycerides.

Figures

Figure 1.

Changes in lipid profiles. Bar chart of mean change from baseline of total cholesterol (A), low-density lipoprotein–associated cholesterol (LDL-C); B), high-density lipoprotein–associated cholesterol (HDL-C; C), triglycerides (D), and Lp(a) (lipoprotein(a); E) after week 3 and week 6 of dosing with placebo (blue bars), nifedipine (green bars), and selective ETA receptor antagonism (red bars). ***P<0.001 for change at week 6 vs baseline; ···P<0.001 for change at timepoint vs placebo and nifedipine; and ·P<0.05 for change at timepoint vs placebo or nifedipine. Analysis by ANOVA. Error bars are SE of mean. Conversion factors for units: cholesterol, LDL-C, and HDL-C in mg/dL to mmol/L, ×0.02586; and triglycerides in mg/dL to mmol/L, ×0.01129.

Figure 2.

Change in circulating PCSK9 (proprotein convertase subtilisin/kexin type 9). Bar chart of mean change in plasma PCSK9 from baseline after week 3 and week 6 of dosing with placebo (blue bars), nifedipine (green bars), and selective ETA (endothelin-A) receptor antagonist (red bars). ***P<0.001 for selective ETA receptor antagonist at week 6 vs baseline; analysis by paired t tests. ·P<0.05 for change at timepoint vs placebo and nifedipine. Analysis by ANOVA. Error bars are SE of mean.

Figure 3.

Change in lipids and circulating PCSK9 (proprotein convertase subtilisin/kexin type 9). Scatter plots of individual percentage changes from baseline in total cholesterol (A), low-density lipoprotein–associated cholesterol (LDL-C); B), high-density lipoprotein–associated cholesterol (HDL-C); C), and triglycerides (D) after 6 weeks of treatment vs individual percentage change in plasma PCSK9. Blue dots denote subjects receiving placebo; green dots denote subjects receiving nifedipine; and red dots denote subjects receiving selective ETA (endothelin-A) receptor antagonist.

Figure 4.

Proposed pathways linking the endothelin system, PCSK9 (proprotein convertase subtilisin/kexin type 9) expression and cholesterol in chronic kidney disease. The liver is the major site of PCSK9 expression with HNF1α (hepatic nuclear factor 1α) and SREBP2 (sterol regulatory element binding protein 2) its principle promoters. Animals studies have shown that insulin binding to hepatocytes prevents nuclear translocation of HNF1α thus reducing PCSK9 transcription. ET-1 (endothelin-1) impairs hepatocyte insulin sensitivity which can be ameliorated by selective ETA receptor antagonism, and so may restore the inhibitory effect of insulin on HNF1α-mediated PCSK9 transcription in hepatocytes. Whether ET-1 has direct effects on HNF1α or SREBP2 in hepatocytes is unknown. Systemic inflammation can increase both hepatic and renal PCSK9 expression with a concurrent reduction in LDL-R (low density lipoprotein receptor) expression and a rise in low-density lipoprotein–associated cholesterol (LDL-C). In the vasculature, ET-1 has proinflammatory effects mediated predominantly through ETA receptor activation. In the kidney, podocyte damage is associated with increased circulating and renal PCSK9 expression, notably localized to proximal tubular cells in murine models. The relevance of renal PCSK9 expression to the circulating PCSK9 pool and lipids needs further clarification. Interestingly, ER (endoplasmic reticulum) stress leads to an upregulation of SREBP2 in renal proximal tubular cells with subsequent apoptosis, but effects on PCSK9 expression here are unexplored. However, selective ETA antagonism has been shown to ameliorate podocyte injury and proximal tubule ER stress suggesting a potential role in renal PCSK9 expression.