mocetinostat and Albuminuria

Antibodies to neutrophil and monocyte myeloperoxidase and proteinase 3 are a feature of anti-neutrophil cytoplasmic antibody vasculitis, a disease with significant morbidity for which new treatments are needed. Mice with a myeloid-specific deletion of the anti-apoptotic protein Mcl1 have reduced numbers of circulating neutrophils. Here, we assessed if myeloid-specific Mcl1 was required in murine anti-myeloperoxidase vasculitis and whether inhibition of myeloperoxidase was protective. In a murine model of anti-neutrophil cytoplasmic antibody vasculitis, induced by anti-myeloperoxidase antibody, mice with a myeloid-specific deletion of Mcl1 were protected from disease. They had fewer crescents, neutrophils, and macrophages in the glomeruli, lower serum creatinine levels and reduced albuminuria compared with controls. At baseline and day six after disease induction they had fewer circulating neutrophils than controls. At day six there were also fewer circulating monocytes. Myeloperoxidase inhibition with AZD5904 had no effect on histological or biochemical parameters of disease, and there was also no reduction in albuminuria at day one, two, five or seven after disease induction. These findings persisted when disease was induced without granulocyte-colony stimulating factor, which increases disease severity. A second myeloperoxidase inhibitor, AZM198, also showed no evidence of an effect, although both AZD5904 and AZM198 inhibited human neutrophil extracellular trap formation in vitro. Thus, our results show that while myeloid-specific Mcl1 is required in this model of anti-myeloperoxidase vasculitis, myeloperoxidase inhibition is not protective.

Topics: Albuminuria; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Apoptosis Regulatory Proteins; Glomerulonephritis; Humans; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neutrophils; Peroxidase; Vasculitis

It is possible that myeloperoxidase (MPO) contributes to the pathogenesis of diabetic nephropathy through the production of reactive oxygen species and HOCl/OCl⁻. In this study, we examined the relationship between renal damage and MPO G-463A gene polymorphism that is associated with its transcription activity in diabetic patients. We evaluated the association between MPO G-463A polymorphism and the prevalence of proteinuria and estimated GFR (eGFR) in 1448 Japanese type 2 diabetic subjects. The prevalence of macroalbuminuria was higher as the number of G alleles increased (GG (7.6%), GA (3.8%), AA (0.0%), p for trend=0.0269). The number of G alleles was significantly associated with macroalbuminuria (odds ratio 2.12, 95%CI 1.06-4.24, p=0.0344) even after adjustment for conventional risk factors. Inversely, eGFR was lower as the number of G alleles increased (GG (76.7±20.7 mL/min/1.73m²), GA (81.0±22.8 mL/min/1.73m²), AA (92.0±23.1 mL/min/1.73m²), p for trend=0.0025) and the number of G allele was an independent risk factor for a low eGFR (β=-0.072, p=0.003). We also examined the association between MPO expression and several stages of renal damage in a high-fat diet-induced diabetic mouse model. The proteinuria-induced increase in MPO expression was markedly enhanced in diabetic mice, and MPO expression was significantly correlated with the severity of kidney damage. In conclusion, it is likely that the G allele of the MPO G-476T polymorphism is a susceptibility allele for renal injury in type 2 diabetic patients.

Topics: 3' Flanking Region; Aged; Albuminuria; Animals; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Japan; Kidney; Male; Mice; Mice, Inbred C57BL; Middle Aged; Peroxidase; Polymorphism, Single Nucleotide; Prevalence; Severity of Illness Index

Coeliac disease is more frequent in IgA nephropathy (IgAN) patients compared to the healthy population. Several hypotheses postulate that food antigens like gluten may be involved in the onset of IgAN.. In this study, we used a recently developed mucosal patch technique to evaluate the rectal mucosal inflammatory reaction to gluten in patients with IgAN (n = 27) compared to healthy subjects (n = 18). The rectal mucosal production of nitric oxide (NO) and release of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were measured. Serum samples were analysed for IgA and IgG antigliadin antibodies (AGA), IgA antibodies against tissue transglutaminase and IgA endomysium antibodies.. Gluten reactivity, defined as increase in MPO and/or NO after gluten exposure, was observed in 8 of 27 IgAN patients. The prevalence of HLA-DQ2 and DQ8 was not increased among gluten-sensitive patients, and the total prevalence among IgAN patients was the same as for the normal population. An elevated serum IgA AGA response was seen in 9 of 27 IgAN patients. The increase in IgA AGA did not correlate with the gluten sensitivity as measured by NO and/or MPO. A specific serum IgG AGA response was seen in one patient only. Antibodies against tissue transglutaminase and endomysium were not observed.. It is concluded that approximately one-third of our IgAN patients have a rectal mucosal sensitivity to gluten, but without signs of coeliac disease, and we hypothesize that such sub-clinical inflammation to gluten might be involved in the pathogenesis of IgAN in a subgroup of patients.

Topics: Adult; Aged; Albuminuria; Autoantibodies; Case-Control Studies; Celiac Disease; Eosinophil Cationic Protein; Female; Gliadin; Glomerulonephritis, IGA; GTP-Binding Proteins; HLA-DQ Antigens; Humans; Immunoglobulin A; Immunoglobulin G; Intestinal Mucosa; Male; Middle Aged; Nitric Oxide; Peroxidase; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases; Young Adult

Topics: Albuminuria; Biomarkers; C-Reactive Protein; Fibrinogen; Humans; Myocardial Infarction; Peroxidase