Inhibition of a novel Dickkopf-1-LDL receptor–related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice

Abstract Background and Aims Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure–lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor–related proteins 5 and 6 (LRP5/6) can directly bind to several G protein–coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. Methods The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. Results Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as β-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. Conclusions These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries. Structured Graphical Abstract Structured Graphical Abstract Role of DKK1 inducing the development of hypertension and organ injury in diabetes. Under normal conditions, LRP5/6 bind to and fine-tune GPCRs to maintain normal GPCR signal transduction and organ homeostasis. Under diseased conditions such as type 2 diabetes, elevated circulating DKK1 induces membrane LRP5/6 endocytosis, which leads to deregulations of GPCRs. For example, deregulation of AT1R activation leads to hypertension, while deregulations of other LRP5/6-interacting GPCRs lead to organ injury, and these can be prevented by an anti-DKK1 neutralizing antibody or MDC that prevents DKK1-induced LRP5/6 endo