Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes
MetadataShow full item record
Aims/hypothesis Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. Methods ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1−/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1 (1 µg, 100 µl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 µl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.). Results Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0±4.2/64.0±4 ng/ml vs 35.9±2.3 ng/ml; p<0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1−/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1±1.6% vs 49.9±0.9%) and renal dysfunction (proteinuria; 89.3±5.0 μg/mg vs 113.3±5.5 μg/mg). Mechanistically, compared with non-diabetic WT mice, the degree of the phosphorylation of mitogen-activated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1−/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1–13) attenuated both cardiac (ejection fraction; 54.0±1.6% vs 72.4±1.0%) and renal (proteinuria; 89.3±5.0 μg/mg vs 53.1±3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8–13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Conclusions/interpretation Overall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with type 1 diabetes independent of a significant impairment in renal function. Furthermore, in mouse models with STZ-induced type 1 diabetes, ANXA1 protects against cardiac and renal dysfunction by returning MAPK signalling to baseline and activating pro-survival pathways (Akt). We propose ANXA1 to be a potential therapeutic option for the control of comorbidities in type 1 diabetes.
AuthorsPurvis, GSD; Chiazza, F; Chen, J; Loiola, RA; Martin, L; Fountoulakis, N; Gnudi, L; Collino, M; Thiemermann, C; Solito, E
- College Publications 
Showing items related by title, author, creator and subject.
Genes and type 2 diabetes: polymorphisms of the EIF2AK3 gene and its relationship to type 2 diabetes mellitus Sudagani, Jaidev (2010)Aims/ Hypothesis: Wolcott- Rallison syndrome (WRS) is a rare autosomal recessively inherited Mendelian disorder. It is characterised by a short trunk compared to arm span, multiple epiphyseal dysplasia, multiple fractures, ...
Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS). Livingstone, SJ; Looker, HC; Akbar, T; Betteridge, DJ; Durrington, PN; Hitman, GA; Neil, HA; Fuller, JH; Colhoun, HM (2015-09-12)AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with ...
Quantification of the type 2 diabetes risk in women with gestational diabetes: a systematic review and meta-analysis of 95,750 women. Rayanagoudar, G; Hashi, AA; Zamora, J; Khan, KS; Hitman, GA; Thangaratinam, S (2016-02-25)AIMS/HYPOTHESIS: Women with gestational diabetes mellitus (GDM) are at risk of developing type 2 diabetes, but individualised risk estimates are unknown. We conducted a meta-analysis to quantify the risk of progression to ...