IL-33 receptor ST2 deficiency attenuates renal ischaemia–reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice

Abstract

AimKidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia–reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2−/−) on renal IRI in euglycaemic and hyperglycaemic mice. MethodsHyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2−/− mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. ResultsUrinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2−/− mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2−/− animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. ConclusionOur data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on alarmins and diabetes in ischaemia-related diseases.