Phosphatidylethanolamine binding protein-4 (PEBP4) is increased in IgA nephropathy and is associated with IgA-positive B-cells in affected kidneys

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a major cause of chronic kidney disease and failure. IgAN is driven by an autoimmune reaction against galactose-deficient IgA1 that results in the generation of autoantibodies and large IgG-IgA immune complexes. Immune complexes accumulate in the glomerular mesangium causing chronic inflammation and renal scarring. A significant proportion of IgAN patients develop end-stage kidney disease and require dialysis or transplantation. Currently, there are no approved specific therapies that can ameliorate the systemic autoimmune reaction in IgAN and no biomarkers that can predict renal inflammation and scarring. In this study, we used shotgun LC-MS/MS proteomics to compare small volumes of urine from healthy subjects and IgAN patients. We identified multiple urine proteins with unknown renal or IgAN function. Our attention was captured by the increase of phosphatidylethanolamine binding protein-4 (PEBP4) in IgAN urine. The function of PEBP4 in IgAN or renal disease is unknown. Increased levels of urine and serum PEBP4 were subsequently validated in different cohorts of IgAN patients and PEBP4 was linked to declining kidney function in IgAN. Strong PEBP4 staining was sporadically seen in IgAN kidney biopsies, colocalising with IgA in glomeruli and in the lumen of kidney tubules. In a small number of IgAN biopsies, PEBP4 colocalised with IgA and CD19 while the increased excretion of PEBP4 in IgAN urine was accompanied by increased excretion of classic B-cell factors BAFF, BCMA and TACI as well as IgA and IgG. PEBP4 is a new IgAN-related protein with unknown function and a likely renal disease marker in urine and serum

Polygenic risk in Type III hyperlipidaemia and risk of cardiovascular disease : An epidemiological study in UK Biobank and Oxford Biobank

Background: Type III hyperlipidaemia (T3HL) is characterised by equimolar increases in plasma triglycerides (TG) and cholesterol in <10% of APOE22 carriers conveying high cardiovascular disease (CVD) risk. We investigate the role of a weighted triglyceride-raising polygenic score (TG.PS) precipitating T3HL. Methods: The TG.PS (restricted to genome-wide significance and weighted by published independent effect estimates) was applied to the Oxford Biobank (OBB, n = 6952) and the UK Biobank (UKB, n = 460,037), to analyse effects on plasma lipid phenotypes. Fasting plasma lipid, lipoprotein biochemistry and NMR lipoprotein profiles were analysed in OBB. CVD prevalence/incidence was examined in UKB. Results: One TG.PS standard-deviation (SD) was associated with 13.0% (95% confidence-interval 12.0–14.0%) greater TG in OBB and 15.2% (15.0–15.4%) in UKB. APOE22 carriers had 19.0% (1.0–39.0%) greater TG in UKB. Males were more susceptible to TG.PS effects (4.0% (2.0–6.0%) greater TG with 1 TG.PS SD in OBB, 1.6% (1.3–1.9%) in UKB) than females. There was no interaction between APOE22 and TG.PS, BMI, sex or age on TG. APOE22 carriers had lower apolipoprotein B (apoB) (OBB; −0.35 (−0.29 to −0.40)g/L, UKB; −0.41 (−0.405 to −0.42)g/L). NMR lipoprotein lipid concentrations were discordant to conventional biochemistry in APOE22 carriers. In APOE22 compared with APOE33, CVD was no more prevalent in similarly hypertriglyceridaemic participants (OR 0.97 95%CI 0.76–1.25), but was less prevalent in normolipidaemia (OR 0.81, 95%CI 0.69–0.95); no differences were observed in CVD incidence. Conclusions: TG.PS confers an additive risk for developing T3HL, that is of comparable effect size to conventional risk factors. The protective effect of APOE22 for prevalent CVD is consistent with lower apoB in APOE22 carriers

A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome

Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-chains of type-IV collagen, the most abundant component of the extracellular glomerular basement membrane (GBM). Currently most AS mouse models are knockout models for one of the collagen-IV genes. In contrast, about half of AS patients have missense mutations, with single aminoacid substitutions of glycine being the most common. The only mouse model for AS with a homozygous knockin missense mutation, Col4a3-p.Gly1332Glu, was partly described before by our group. Here, a detailed in-depth description of the same mouse is presented, along with another compound heterozygous mouse that carries the glycine substitution in trans with a knockout allele. Both mice recapitulate essential features of AS, including shorten lifespan by 30-35%, increased proteinuria, increased serum urea and creatinine, pathognomonic alternate GBM thinning and thickening, and podocyte foot process effacement. Notably, glomeruli and tubuli respond differently to mutant collagen-IV protomers, with reduced expression in tubules but apparently normal in glomeruli. However, equally important is the fact that in the glomeruli the mutant α3-chain as well as the normal α4/α5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35 kDa C-terminal fragment. These mouse models represent a good tool for better understanding the spectrum of molecular mechanisms governing collagen-IV nephropathies and could be used for pre-clinical studies aimed at better treatments for AS

Phosphatidylethanolamine binding protein-4 (PEBP4) is increased in IgA nephropathy and is associated with IgA-positive B-cells in affected kidneys

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a major cause of chronic kidney disease and failure. IgAN is driven by an autoimmune reaction against galactose-deficient IgA1 that results in the generation of autoantibodies and large IgG-IgA immune complexes. Immune complexes accumulate in the glomerular mesangium causing chronic inflammation and renal scarring. A significant proportion of IgAN patients develop end-stage kidney disease and require dialysis or transplantation. Currently, there are no approved specific therapies that can ameliorate the systemic autoimmune reaction in IgAN and no biomarkers that can predict renal inflammation and scarring. In this study, we used shotgun LC-MS/MS proteomics to compare small volumes of urine from healthy subjects and IgAN patients. We identified multiple urine proteins with unknown renal or IgAN function. Our attention was captured by the increase of phosphatidylethanolamine binding protein-4 (PEBP4) in IgAN urine. The function of PEBP4 in IgAN or renal disease is unknown. Increased levels of urine and serum PEBP4 were subsequently validated in different cohorts of IgAN patients and PEBP4 was linked to declining kidney function in IgAN. Strong PEBP4 staining was sporadically seen in IgAN kidney biopsies, colocalising with IgA in glomeruli and in the lumen of kidney tubules. In a small number of IgAN biopsies, PEBP4 colocalised with IgA and CD19 while the increased excretion of PEBP4 in IgAN urine was accompanied by increased excretion of classic B-cell factors BAFF, BCMA and TACI as well as IgA and IgG. PEBP4 is a new IgAN-related protein with unknown function and a likely renal disease marker in urine and serum