The Role of PCSK9 in Nephrotic Syndrome-Associated Hypercholesterolemia
PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Is there a role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome (NephSyn)?
PCSK9 and plasma lipids were studied in NephSyn patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice), and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of NephSyn.
Upon remission of their disease, patients with NephSyn (mean age 37.6 years, mean baseline total cholesterol 298 mg/dl, low-density lipoprotein cholesterol [LDL-C] 178 mg/dl, high-density lipoprotein cholesterol [HDL-C] 81 mg/dl, triglycerides 191 mg/dl, PCSK9 348 ng/ml) resolved the hyperlipidemia (mean total cholesterol 197 mg/dl, LDL-C 101 mg/dl, HDL-C 69 mg/dl, triglycerides 136 mg/dl) and reduced plasma PCSK9 by 14%. Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Knockout of Pcsk9 ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40-50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of LDL-C (from 9% in vehicle-treated Flox mice to 47% after NTS treatment) was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS).
Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of NephSyn. These data suggest that PCSK9 inhibitors may be beneficial in patients with NepSyn–associated hypercholesterolemia.
Finding a novel renal podocyte/hepatic axis in this elegant study is not surprising considering the cross-sectional studies in humans showed plasma PCSK9 to be increased 50-60% in proteinuric/nephrotic patients in comparison with control subjects. The marked reduction in total cholesterol and LDL-C and decrease in HDL-C with only a 14% reduction in PCSK9 levels in the patients suggests other mechanisms including enhanced hepatic synthesis of cholesterol and increased production of apoB-containing lipoproteins resulting from hepatic stimulus by loss of apoB in the urine and improved clearance of HDL-C by hepatic receptors.
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