Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome

Molina‐Jijón, Eduardo; Gambut, Stéphanie; Macé, Camille; Ávila-Casado, Carmen; Clement, Lionel C.

doi:10.1016/j.kint.2020.06.045

Cited by 19 publications

(13 citation statements)

References 39 publications

(34 reference statements)

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“…The results of a very recent study of Molina-Jijon et al showed that the kidney PCSK9 expression was enhanced in the collecting duct of nephrotic patients and animals, supporting the hypothesis that the kidney could be a major source for plasma PCSK9 in nephrotic syndrome. In our study, the vast majority of our patients were not nephrotic [47].…”

Section: Discussionmentioning

confidence: 50%

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Dounousi

Tellis

Pavlakou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Proprotein convertase subtilisin/kexin 9 (PCSK9) plays an important role in lipid metabolism while available literature regarding its involvement in the pathogenesis of atherosclerosis and in the expression of genes associated with apoptosis and inflammation is constantly increasing. Patients with chronic kidney disease (CKD) experience disproportionately increased cardiovascular morbidity and mortality due to dyslipidemia, accelerated atherosclerosis, inflammation, oxidative stress, and other risk factors. In the present cross-sectional study, we investigated the possible association of serum PCSK9 levels with markers of inflammation, oxidative stress, and endothelial damage in patients with CKD. Patients and Methods. Ninety-two patients with CKD stages II-ΙV (eGFR CKD-EPI 47.3 ± 25.7 ml/min/1.73 m2, mean age 66 years, 51 men) were included in the study. Plasma PCSK9 levels were correlated with comorbidities (arterial hypertension, diabetes mellitus, and history of cardiovascular disease), renal function indices (eGFR, proteinuria–UPR/24 h), lipid parameters (LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), APO-A1, and APO-B), and soluble biomarkers of inflammation, oxidative stress, and endothelial damage (hs-CRP, fibrinogen, 8-epiPGF2a, ox-LDL, IL-6, TNF-α, sICAM-1, and sVCAM-1). Results. The mean plasma value of PCSK9 was 278.1 ng/ml. PCSK9 levels showed direct correlation with serum triglycerides ( p = 0.03 ), Lp(a) ( p = 0.01 ), and sICAM-1 levels ( p = 0.03 ). There was no significant correlation between PCSK9 levels and indices of the renal function, other lipid profile parameters, inflammatory markers, or comorbidities. Multiple regression analysis showed a significant effect of Lp(a) on PCSK9 levels, and for each unit of higher Lp(a), an increase by 3.082 is expected (95% CI: 0.935-5.228, p = 0.006 ). At the same time, patients receiving statins are expected to have on average 63.8 ng/ml higher PCSK9 values compared to patients not receiving statins (95% CI: 14.6-113.5, p = 0.012 ). Conclusion. Plasma levels of PCSK9 in nondialysis CKD patients are correlated with endothelial dysfunction and lipid metabolism parameters. Statin intake increases PCSK9 levels significantly in this patient population. PCSK9 levels are not correlated with the severity of kidney disease. Major prospective studies are necessary to investigate the role of PCSK9 in the atherosclerotic cardiovascular outcome in CKD.

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Section: Discussionmentioning

confidence: 50%

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Dounousi

Tellis

Pavlakou

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Altogether, inhibition of PCSK9, either by PSCSK9 inhibitors or heparin mimetics at an early stage of nephrotic syndrome, might reduce or delay the development of and also the progression of kidney damage. 52 In conclusion, our study provides novel insight on how hypersulfated HSPG-PCSK9 complex formation might decrease the hepatic uptake of lipoproteins, leading to dyslipidemia in proteinuric conditions. It also opens new venues for future development of heparin mimetics as PCSK9 inhibitors.…”

Section: Discussionmentioning

confidence: 76%

“…33,42,51 Interestingly, a recent study published by Molina-Jijon et al showed that PCSK9-expressed and secreted by renal cortical collecting duct epithelial cellsinitiates hypercholesterolemia in nephrotic syndrome in rodents. 52,53 On the contrary, Adriamycin-treated rat model is a pure proteinuria model with no signs of edema, albuminemia, or hypertension and with unaltered serum creatinine and creatinine clearance. These animals show no other signs of nephrotic syndrome, except dyslipidemia, without changes in expression of hepatic LDLR and PCSK9 plasma levels.…”

Section: Discussionmentioning

confidence: 99%

Proteinuria converts hepatic heparan sulfate to an effective proprotein convertase subtilisin kexin type 9 enzyme binding partner

Shrestha

Yazdani

Vivès

et al. 2021

Kidney International

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Chronic kidney disease (CKD) is a global health problem affecting >10% of the people worldwide. 1 Cardiovascular diseases (CVDs) are the leading cause of mortality in CKD. 2,3 Incidence of coronary heart disease is 40% in end-stage CKD, and CVD-related mortality is 10 to 30 times higher than in the general population of same sex, age, and race. 3,4 Higher risk of CVD in CKD is largely due to anomalies in lipoprotein metabolism, represented by high plasma triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), lipoprotein-a, and low high-density lipoprotein cholesterol (HDLc) levels. The severity of dyslipidemia in CKD depends on level of proteinuria 5,6 and stage of kidney disease. 2,7

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“…Indeed, glomerulonephritis patients showed a greater (albeit non-significant) reduction in proteinuria. This can be explained by lipid damage recovery in glomerulus with PCSK9i administration, but also by inhibition of the newly described mechanism implicated in the dysregulation of dyslipidemia in proteinuric states [12,17,18]. Note that achieving the LDL-C target is likely to be even more difficult in nephrotic syndrome, which opens a clinical path to preferential PCSK9i prescription in this population [29].…”

Section: Discussionmentioning

confidence: 99%

“…Nephrotic syndrome has been associated with a particularly dysregulated lipid metabolism. In this respect, new observations have likened PCSK9 expression in the cortical collecting ducts of primary glomerulonephritis patients to hypercholesterolemia, proposing the kidney, as a source of PCSK9, as a first-line therapeutic target for dyslipidemia in this population [17,18]. Recent rat-based studies have also shown that proteinuria can induce hypersulfated hepatic heparan sulfate side chains of heparan sulfate proteoglycan, increasing the affinity to PCSK9 in sinusoids, and thus worsening dyslipidemia [19].…”

Section: Introductionmentioning

confidence: 99%

Proteinuria-Lowering Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Chronic Kidney Disease Patients: A Real-World Multicentric Study

et al. 2021

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Control of dyslipidemia in chronic kidney disease (CKD) is not always guaranteed with statins and/or ezetimibe. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have opened up a new era in lipid control, but their effect on renal function and proteinuria in real life have not yet been evaluated. The aim of the present study was to analyze the evolution of renal function and proteinuria in a cohort of CKD patients treated with PCSK9i. This retrospective multicentric cohort study included CKD patients treated with PCSK9i. Baseline epidemiological data, comorbidities and laboratory findings (including estimated glomerular filtration rate [eGFR], proteinuria and lipid profile) were collected. The evolution of renal function, proteinuria and lipid profile was analyzed during the 1-year follow-up. The cohort included 76 patients (68% male, mean age 66 ± 10 years). The mean baseline creatinine was 1.55 ± 0.77 mg/dL, and the mean eGFR was 52 ± 22 mL/min/1.73 m2. Reductions in LDL-cholesterol, total cholesterol and triglycerides during the first month were 51 ± 25%, 32 ± 25% and 11 ± 40%, respectively, levels that remained stable throughout the first year (p < 0.001 for LDL-cholesterol and total cholesterol trends and p = 0.002 for triglyceride trend). During follow-up, proteinuria improved from 57 (9–481) to 30 (7–520) mg/g (p = 0.021). In addition, eGFR remained stable, and no adverse events were reported. In our cohort, dyslipidemia treatment with PCSK9i was associated with decreased proteinuria in CKD patients, an effect that might be due to reduced lipid nephrotoxicity. Clinical trials are needed to further investigate whether this impact on proteinuria can significantly slow CKD progression in the long term.

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Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome

Cited by 19 publications

References 39 publications

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Proteinuria converts hepatic heparan sulfate to an effective proprotein convertase subtilisin kexin type 9 enzyme binding partner

Proteinuria-Lowering Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Chronic Kidney Disease Patients: A Real-World Multicentric Study

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