New Agents to Reduce Cholesterol Levels: Implications for Nephrologists

Lucia Del Vecchio; Ivano Baragetti; Francesco Locatelli

Disclosures

Nephrol Dial Transplant. 2020;35(2):213-218. 

In This Article

Proprotein Convertase Subtilisin/Kexin Type 9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is highly expressed in the liver and less in the bowel, kidney and brain. It induces the degradation of the LDL receptor (LDL-R) by targeting it for lysosomal destruction. PCSK9 expression is enhanced in response to low intracellular cholesterol levels by two transcription factors, the sterol regulatory element-binding protein-2 (SREBP-2) and the hepatocyte nuclear factor-1α, through binding to the SRE-1 motif of the promoter of PCSK9.[22]

PCSK9 is a zymogen of 692 amino acids constituted by a signal peptide, a pro-segment, a catalytic domain and a C-terminal domain.[23] After its transduction, it is translocated into the endoplasmic reticulum together with the LDL-R[24] and then in the Golgi's apparatus through Sec24A.[25] The serine protease catalytic activity of PCSK9 cleaves the N-terminal prodomain;[26] this causes a folding of PCSK9 that binds to the first epidermal growth factor-like repeat (EGF-A) of the LDL-R,[27] leading to the internalization of both in endocytic clathrin-coated vesicles and transferring towards lysosomal degradation.

The final result of the interaction of PCSK9 with the EGF-A domain of the LDL-R is a reduction of LDL-R recycling, a reduction of the total LDL-binding capacity of the liver and an increase in LDL-C.[28]

Notably, despite the fact that the PCSK9 gene is overexpressed in the course of CKD,[29] its plasma concentrations are not influenced by renal function.[30,31] Indeed, PCSK9 has the same catabolic destiny of its substrate LDL-R in all the tissues other than the kidney, also through furin and probably the amyloid β precursor-like protein 2.[32] Accordingly, PCSK9 levels have been found to be increased in CKD patients and inversely correlated to estimated glomerular filtration rate (eGFR); HD decreases PCSK9 levels to values similar to those of healthy subjects.[33] However, the determination of PCSK9 levels in larger cohorts of CKD patients did not confirm the relationship.[30,31]

processing....