Interleukin-1β Inhibition for Chronic Kidney Disease in Obese Mice With Type 2 Diabetes

Inflammasome-driven release of interleukin(IL)-1β is a central element of many forms of sterile inflammation and has been evident to promote the onset and progression of diabetic kidney disease. We microdissected glomerular and tubulointerstitial samples from kidney biopsies of patients with diabetic kidney disease and found expression of IL-1β mRNA. Immunostaining of such kidney biopsies across a broad spectrum of diabetic kidney disease stages revealed IL-1β positivity in a small subset of infiltrating immune cell. Thus, we speculated on a potential of IL-1β as a therapeutic target and neutralizing the biological effects of murine IL-1β with a novel monoclonal antibody in uninephrectomized diabetic db/db mice with progressive type 2 diabetes- and obesity-related single nephron hyperfiltration, podocyte loss, proteinuria, and progressive decline of total glomerular filtration rate (GFR). At 18 weeks albuminuric mice were randomized to intraperitoneal injections with either anti-IL-1β or control IgG once weekly for 8 weeks. During this period, anti-IL-1β IgG had no effect on food or fluid intake, body weight, and fasting glucose levels. At week 26, anti-IL-1β IgG had reduced renal mRNA expression of kidney injury markers (Ngal) and fibrosis (Col1, a-Sma), significantly attenuated the progressive decline of GFR in hyperfiltrating diabetic mice, and preserved podocyte number without affecting albuminuria or indicators of single nephron hyperfiltration. No adverse effect were observed. Thus, IL-1β contributes to the progression of chronic kidney disease in type 2 diabetes and might therefore be a valuable therapeutic target, potentially in combination with drugs with different mechanisms-of-action such as RAS and SGLT2 inhibitors

A hexanucleotide repeat upstream of eotaxin gene promoter is associated with asthma, serum total IgE and plasma eotaxin levels

Background: Eotaxin (CCL11) is a small protein produced in the lungs of patients with asthma, and is a potent chemoattractant for eosinophils. Aim: To elucidate the role of eotaxin in asthma by an association study of functional and novel eotaxin polymorphisms in case-control and family-based study designs. Methods:Eotaxin +67G/A, -384A/G and -426C/T single-nucleotide polymorphisms and a hexanucleotide (GAAGGA)n repeat 10.9 kb upstream of the gene were genotyped in a cohort of age, sex and ethnically matched patients with asthma (n = 235) and healthy controls (n = 239), and also in a study population of 230 families with asthma recruited from north/northwest India. Total serum IgE (TsIgE) and plasma eotaxin levels were measured using ELISA. Results: +67G/A polymorphism was found to be significantly associated with asthma in case-control (p = 0.009) and family-based studies (p = 0.006). Its functional role, as it was correlated with plasma eotaxin levels (p = 0.006), was also demonstrated. Further, -384C/T single-nucleotide polymorphism was found to be significantly associated with log10 TsIgE (p = 0.016 in case-control and p = 0.018 in families) and eotaxin levels (p = 0.007). Most interestingly, for the first time, a highly significant association of the newly studied (GAAGGA)n hexanucleotide repeat with asthma (p = 3×10-6), log10TsIgE (p = 0.006) and eotaxin levels (p = 0.004) was observed. G_A_C_8 was also identified as an important risk haplotype associated with high TsIgE and plasma eotaxin levels. Conclusions: This study provides further evidence that eotaxin polymorphisms are associated with the development of asthma by regulating eotaxin levels and reinforces towards the scanning of other chemokine genes present at 17q21 locus for their association with asthma and related phenotypes