Increased renal PCSK9 expression may be partly responsible for the elevated serum PCSK9 level and hypercholesterolemia in primary nephrotic syndrome

The molecular mechanisms underlying hypercholesterolemia in nephrotic syndrome (NS) remain incompletely understood. Previous studies have shown that patients with NS exhibit increased hepatic expression and circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), which contribute to hypercholesterolemia by promoting hepatic low-density lipoprotein receptor (LDLR) degradation and reducing low-density lipoprotein (LDL) clearance. However, the relationships among circulating PCSK9, renal PCSK9 expression, and hypercholesterolemia in primary nephrotic syndrome (PNS) remain unclear. To investigate the associations of circulating PCSK9 with renal PCSK9 expression and hypercholesterolemia in PNS, we enrolled 56 patients with PNS and 48 patients with isolated hematuria (IH). Serum PCSK9 levels were significantly higher in patients with PNS than in those with IH [11.46 (9.31–13.76) ng/mL vs. 6.61 (4.50–8.31) ng/mL, P < 0.0001]. Immunohistochemical analysis further demonstrated increased PCSK9 expression in renal tubular epithelial cells of patients with PNS compared with the IH group. Furthermore, only in patients with PNS were circulating PCSK9 levels positively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and 24-hour urinary protein excretion (24 h-UPQ), a potential stimulus for renal PCSK9 expression. These findings suggest that hypercholesterolemia and elevated serum PCSK9 levels in PNS patients may be partially explained by increased renal PCSK9 expression, which may be associated with the stimulation of proteinuria on renal tubules.