Increased serum PCSK9 levels are associated with renal function impairment in patients with type 2 diabetes mellitus

Abstract

Purpose: The purpose of this study was to investigate the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and renal function impairment in type 2 diabetes mellitus (T2DM) patients.

Methods: PCSK9 levels were measured in T2DM patients, streptozotocin plus high-fat diet (STZ + HFD) mice, human proximal tubular epithelial (HK-2) cells treated with high glucose plus palmitic acid (HGPA) and the corresponding control groups. The T2DM patients were further divided into three groups according to serum PCSK9 levels. An analysis of clinical data was conducted, and a binary logistic regression model was used to test the relationship between potential predictors and urine albumin/urine creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR).

Results: PCSK9 levels were higher in the DM group than in the control group in humans, mice and HK-2 cells. The systolic blood pressure (SBP), serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), and urine α1-MG/urine creatinine ratio (UαCR) values in PCSK9 tertile 3 were significantly higher than those in PCSK9 tertile 1 (p < 0.05). The DBP and UACR values were significantly higher in PCSK9 tertile 3 than in PCSK9 tertile 1 and PCSK9 tertile 2 (both p < 0.05). In addition, URCR values were significantly higher in PCSK9 tertile 3 and PCSK9 tertile 2 than in PCSK9 tertile 1 (both p < 0.05). Serum PCSK9 levels were positively correlated with SBP, Scr, BUN, TG, URCR, UαCR and UACR but inversely correlated with eGFR. In STZ + HFD mice, serum PCSK9 levels were positively correlated with Scr, BUN and UACR, which was consistent with the findings in the patients. A logistic regression model revealed that serum PCSK9 is an independent risk factor for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m². The ROC curve showed that 170.53 ng/mL and 337.26 ng/mL PCSK9 were the best cutoff values for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m², respectively.

Conclusion: Serum PCSK9 levels are associated with renal function impairment in T2DM patients and in some patients lower PCSK9 may be helpful to decrease chronic kidney disease.

Keywords: Proprotein convertase subtilisin/kexin type 9; Type 2 diabetes mellitus; estimated glomerular filtration rate; urine albumin/urine creatinine ratio.

Figure 1.

Study workflow.

Figure 2.

PCSK9 levels are elevated in DM. (A) Serum PCSK9 levels in T2DM patients and healthy control individuals. (B) Serum PCSK9 levels in STZ + HFD mice and control mice. (C) PCSK9 mRNA levels in kidney tissue of STZ + HFD mice and control mice. (D and E) Representative Western blot (left panel) and bar graph analysis (right panel) of PCSK9 levels in kidney tissue of STZ + HFD mice and control mice. (F and G) Representative immunohistochemical staining (left panel) and bar graph analysis (right panel) of PCSK9 levels in kidney tissue of STZ + HFD mice and control mice. Scale bar: 100 μm. (H) PCSK9 mRNA levels in HK-2 cells with HGPA and the control cells. (I and J) Representative Western blot and bar graph analysis of PCSK9 levels in HK-2 cells with HGPA and the control cells. *p < 0.05, **p < 0.01.

Figure 3.

Serum PCSK9 levels were significantly associated with several renal function indicators in T2DM patients. Serum PCSK9 levels were positively correlated with Scr (A), BUN (B), URCR (C), UαCR (D) and UACR (E) but inversely correlated with eGFR (F).

Figure 4.

A ROC curve was used to calculate the AUC of individual PCSK9 levels to discriminate between abnormal UACR and eGFR. (A) The most effective PCSK9 cutoff value for UACR in T2DM patients was 170.53 ng/mL. (B) For diagnosing abnormal eGFR, the value was 337.26 ng/mL.