Credit: NPG

Hypercholesterolaemia is a characteristic of nephrotic syndrome that likely contributes to the increased cardiovascular risk associated with the disease; however, therapies to reduce cholesterol levels in affected patients are lacking. New findings show that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with plasma cholesterol levels in nephrotic syndrome. “Nephrotic syndrome is associated with a profound degree of hypercholesterolaemia,” says researcher Sudha Biddinger. “In this study, we show that this is due, in part, to PCSK9. PCSK9 is increased in mice and humans with nephrotic syndrome, and the ablation of Pcsk9 in mice with nephrotic syndrome markedly reduces hypercholesterolaemia and produces a more benign lipoprotein profile.”

To examine the association between PCSK9 and hypercholesterolaemia in nephrotic syndrome, Biddinger and colleagues first assessed PCSK9 levels in plasma from affected patients and mouse models of nephrotic syndrome. “PCSK9 is known in other contexts to disrupt the clearance of LDL particles by degrading the LDL receptor,” explains Mary Haas, a researcher involved in the study. “We therefore hypothesized that it could be playing a similar role in nephrotic syndrome–associated hypercholesterolaemia.” The researchers found that plasma PCSK9 levels were increased 7–24-fold in two mouse models of acute nephrotic syndrome — one induced by nephrotoxic serum and the other induced by podocyte apoptosis — compared to levels in control mice, and that PCSK9 levels were associated with increased levels of LDL cholesterol.

The findings in mice corresponded to findings from an analysis of PCSK9 and cholesterol levels in 50 patients with nephrotic syndrome. “We measured plasma PCSK9 levels in patients with nephrotic syndrome at two distinct time points: during the disease state and during remission,” explains Haas. “We found decreases in PCSK9 upon remission of the disease, suggesting that the findings elucidated from the mouse studies are conserved in humans.”

These results are particularly exciting given the recent FDA approval of PCSK9 inhibitors

Examination of the mechanisms by which PCSK9 levels were elevated showed that podocyte injury led to increased hepatic secretion and decreased clearance of plasma PCSK9, and decreased expression of hepatic LDL receptor protein. These findings are in line with the known role of PCSK9 in LDL receptor lysosomal degradation.

To dissect the role of PCSK9 in nephrotic syndrome–associated hypercholesterolaemia, Biddinger and coworkers explored the effect of liver-specific Pcsk9 ablation on cholesterol levels in mice with nephrotoxic serum-induced nephrotic syndrome. They found that mice lacking hepatic Pcsk9 had a 40–50% reduction in plasma cholesterol and exhibited a more atheroprotective lipoprotein profile than mice with intact Pcsk9. The researchers say that this finding identifies PCSK9 as an important participant in nephrotic syndrome-associated dyslipidaemia and as a therapeutic target.

“These data reveal the existence of a renal–hepatic axis that regulates plasma cholesterol via PCSK9, linking podocyte injury to hypercholesterolaemia,” says Haas. “The results are particularly exciting given the recent FDA approval of PCSK9 inhibitors for the treatment of high cholesterol.”