S TAN 1, M ZIEMANN 2, A LASKOWSKI 1, M COUGLAN 1,3
1Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia, 2Deakin University, School of Life and Environmental Sciences, Geelong, Australia, 3Baker Heart and Diabetes Institute, Melbourne, Australia
Aim: To investigate whether valproic acid (VPA) attenuates diabetic kidney disease via inhibition of the complement pathways.
Background: We have previously shown that the complement C5a-C5a receptor 1 (C5aR1) pathway is activated in diabetes and is an important mediator of renal injury. Importantly, this pathway is not targeted by conventional therapies, the renin-angiotensin blockers, to treat diabetic kidney disease. VPA is a histone deacetylase (HDAC) inhibitor and in vitro studies have shown that VPA attenuates hyperglycaemia-induced gene expression of the complement pathways in the liver cells. However, whether VPA mediates renoprotection via inhibition of the complement pathways is not known.
Methods: Diabetes was induced in 6-week-old C57BL/6 mice via five daily injection of streptozotocin (STZ; 55mg/kg/day). After two weeks, VPA was administered via oral gavage at 150mg/kg/day for eight weeks. Kidneys were assessed for renal dysfunction and injury. The complement activation end-product, C5a, was measured in the urine by ELISA.
Results: Treatment of VPA reduced HbA1c and kidney hypertrophy in diabetes. Albuminuria and glomerulosclerosis were attenuated by VPA treatment in STZ mice. Urinary complement C5a was decreased in VPA-treated diabetic mice.
Conclusion: We demonstrates for the first time that VPA attenuated complement activation in STZ mice, concomitant with an improvement in diabetes and renal injury. As complement pathways are not targeted by current therapies for diabetic kidney disease, repurposing clinically approved drugs such as VPA that inhibits complement activation, may be of clinical significance.
Dr Tan is a research fellow at the Department of Diabetes, Monash University and the recipient of a JDRF Advanced Postdoctoral Fellowship. She is currently working on identifying new therapeutic targets for diabetic kidney disease with a specific focus on the role of the complement system.