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Deprecated: Implicit conversion from float 294.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Circulation 2016 ; 134 (1): 61-72 Nephropedia Template TP
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The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia: Haas et al: PCSK9 in Nephrotic Syndrome Hypercholesterolemia #MMPMID27358438
Haas ME; Levenson AE; Sun X; Liao WH; Rutkowski JM; de Ferranti SD; Schumacher VA; Scherer PE; Salant DJ; Biddinger SB
Circulation 2016[Jul]; 134 (1): 61-72 PMID27358438show ga
Background: In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome. Methods and Results: Both nephrotoxic serum (NTS) treatment, which induces immune-mediated damage of the podocyte, and genetic ablation of the podocyte produced hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9 in mice. Conversely, patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 upon remission of their disease (p<0.05, n=47-50). The induction of plasma PCSK9 in nephrotic syndrome appeared to be due to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9 ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the proportion of LDL-associated cholesterol (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). Conclusions: Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia.