Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate - PCSK9 Interaction

BackgroundDyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.MethodsUninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats.ResultsCompared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes.ConclusionsProgressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

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Production of Methylguanidine in Dogs with Acute and Chronic Renal Failure

Clinical Science ◽

10.1042/cs0770637 ◽

1989 ◽

Vol 77 (6) ◽

pp. 637-641 ◽

Cited By ~ 2

Author(s):

David P. Brooks ◽

Gerald R. Rhodes ◽

Paul Woodward ◽

Venkata K. Boppana ◽

Francine M. Mallon ◽

...

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Renal Insufficiency ◽

Solid Phase ◽

Plasma Concentrations ◽

Tubular Secretion ◽

Plasma Creatinine ◽

Creatinine Concentration ◽

Plasma Creatinine Concentration ◽

Renal Tubular

1. Methylguanidine is a suspected uraemic toxin that accumulates in renal failure 2. We measured methylguanidine in the plasma of dogs with acute ischaemic-induced renal failure and in the plasma and urine of dogs with spontaneous chronic renal insufficiency, using a highly sensitive method involving solid-phase extraction followed by h.p.l.c. with post-column fluorescence detection 3. Constriction of the remaining renal artery of four uninephrectomized dogs for 90 min resulted in a significant (P < 0.01) increase in plasma creatinine concentration after 24 h (from 113 ± 3 to 303 ± 50 μmol/l; mean ± sem). Over the next 14 days, plasma creatinine fell towards baseline concentrations. Plasma methylguanidine also increased significantly (P < 0.05) 24 h after renal occlusion (from 0.16 ± 0.04 to 0.86 ± 0.32 μmol/l) and showed a similar pattern to the plasma creatinine concentration 4. In a further four dogs, administration of mannitol (2 g/kg) at the time of reperfusion significantly attenuated these responses 5. Dogs with chronic renal failure demonstrated increased plasma concentrations and urinary excretion of methylguanidine, and the levels appeared to be related to the severity of renal insufficiency. Thus, the dogs with the highest plasma creatinine concentrations and lowest creatinine clearances had the highest plasma methylguanidine concentrations. The clearance of methylguanidine exceeded that of creatinine, indicating that the toxin undergoes renal tubular secretion.

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HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure

AJP Renal Physiology ◽

10.1152/ajprenal.00074.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. F539-F544 ◽

Cited By ~ 26

Author(s):

K. Liang ◽

C. H. Kim ◽

N. D. Vaziri

Keyword(s):

Renal Failure ◽

Total Cholesterol ◽

Reductase Activity ◽

Plasma Cholesterol ◽

Ldl Receptor ◽

Hdl Cholesterol ◽

Hmg Coa Reductase ◽

Cholesterol Ratio ◽

Plasma Lcat ◽

Coa Reductase

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF ( nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg·kg−1·day−1) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7α-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7α-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7α-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.

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Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

Current Drug Targets ◽

10.2174/1389450120666190214141626 ◽

2019 ◽

Vol 20 (10) ◽

pp. 1029-1040 ◽

Cited By ~ 1

Author(s):

Xinjie Lu

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Structure And Function ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Proprotein Convertase ◽

Novel Target ◽

New Treatments ◽

And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

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Development of UHPLC/Q-TOF Analysis Method to Screen Glycerin for Direct Detection of Process Contaminants 3-Monochloropropane-1,2-diol Esters (3-MCPDEs) and Glycidyl Esters (GEs)

Molecules ◽

10.3390/molecules26092449 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2449

Author(s):

Lauren Girard ◽

Kithsiri Herath ◽

Hernando Escobar ◽

Renate Reimschuessel ◽

Olgica Ceric ◽

...

Keyword(s):

Renal Failure ◽

Solid Phase ◽

Direct Detection ◽

Screening Method ◽

Extraction Procedure ◽

Biodiesel Production ◽

Food Contaminants ◽

Exact Mass ◽

Glycidyl Esters

The U.S. Food and Drug Administration’s (FDA′s) Center for Veterinary Medicine (CVM) has been investigating reports of pets becoming ill after consuming jerky pet treats since 2007. Renal failure accounted for 30% of reported cases. Jerky pet treats contain glycerin, which can be made from vegetable oil or as a byproduct of biodiesel production. Glycidyl esters (GEs) and 3-monochloropropanediol esters (3-MCPDEs) are food contaminants that can form in glycerin during the refining process. 3-MCPDEs and GEs pose food safety concerns, as they can release free 3-MCPD and glycidol in vivo. Evidence from studies in animals shows that 3-MCPDEs are potential toxins with kidneys as their main target. As renal failure accounted for 30% of reported pet illnesses after the consumption of jerky pet treats containing glycerin, there is a need to develop a screening method to detect 3-MCPDEs and GEs in glycerin. We describe the development of an ultra-high-pressure liquid chromatography/quadrupole time-of-flight (UHPLC/Q-TOF) method for screening glycerin for MCPDEs and GEs. Glycerin was extracted and directly analyzed without a solid-phase extraction procedure. An exact mass database, developed in-house, of MCPDEs and GEs formed with common fatty acids was used in the screening.

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INF2 p.Arg214Cys mutation in a Chinese family with rapidly progressive renal failure and follow-up of renal transplantation: case report and literature review

BMC Nephrology ◽

10.1186/s12882-021-02254-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Wenbo Zhao ◽

Xinxin Ma ◽

Xiaohao Zhang ◽

Dan Luo ◽

Jun Zhang ◽

...

Keyword(s):

Renal Failure ◽

Renal Disease ◽

Autosomal Dominant ◽

Mutational Analysis ◽

Elevated Serum ◽

Chinese Family ◽

Progressive Renal Failure ◽

Rapidly Progressive Renal Failure ◽

Stage Renal Disease ◽

End Stage

Abstract Background Heterozygous mutations in the inverted formin 2 (INF2) gene are related to secondary focal segmental glomerulosclerosis (FSGS), a rare secondary disease associated with rapidly progressive renal failure. Case presentation We report a patient with familial autosomal INF2 mutation manifesting nephritic syndromes and elevated serum creatinine levels. Mutational analysis revealed an autosomal dominant (AD) inheritance pattern and a mutation in exon 4 (p.Arg214Cys) of INF2 as the likely cause, which has not been previously described in an Asian family. The patient progressed to end-stage renal disease (ESRD) and received hemodialysis. His mother had undergone renal transplant 3 years earlier, and his grandmother had carried the p.Arg214Cys mutation for more than 80 years without any sign of renal dysfunction. Conclusions This is the first report to identify an association between a familial autosomal dominant INF2 p.Arg214Cys mutation and rapidly progressive renal disease in an Asian family. INF2 mutation analysis should not be restricted to individuals without family history of FSGS, rather it should also be performed on individuals for whom drug-based therapies are not effective. In this case, kidney transplant is an effective alternative.

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