With more than 422 million people worldwide with diabetes and 60 million in the European region, diabetes and, especially the complications associated, are becoming a major public health problem with significant social and economic burden. Among all the complications, Diabetic kidney disease (DKD) can explain most excess mortality associated with diabetes. DKD is the most common cause of the end-stage renal disease (ESRD). Regardless of intensive treatments with hyperglycaemic control, blood pressure control and the use of renin-angiotensin system blockades the prevalence of DKD remains high and more than 40% of diabetic patients develop the disease. For this reason, better diagnostic tools, predictive markers, and treatment options are still urgently needed. Although over the last years the understanding of DKD has been improved, the development of new therapies in DKD is facing three major challenges; First, it is still unknown when a diabetic patient is prone to develop DKD. We do not have sensitive and specific biomarkers to identify high risk patients and genetic factors with strong association have not been identified. Secondly, it is unknown when DKD is initiated. A metabolic disease which normally appears in adulthood lives nonetheless may have its origin in an abnormal development due to maternal metabolic disturbances. And lastly, there is the lack of a good preclinical model that can recapitulate the disease.
Several studies have described epigenetic changes in DKD. However, none of these studies have been able to proof that metabolic alterations during kidney development can give rise to changes in the landscape of the kidney epigenetic profile that may influence the diabetic outcome.
Although human epidemiological studies have shown that hyperglycaemia during pregnancy may be a prevailing factor that contributes to the develop of DKD of the offspring in adulthood, little is known about the molecular basis of this link and how the hyperglycaemic state may drive epigenetic alterations that result in DKD. Taking this into consideration, EPIORGABOLISM proposed to test if DKD is promoted by the metabolic alterations occurring in development due to hyperglycaemia episodes which could affect the DNA methylation profile, using the innovative in vitro system of 3 dimensional (3D) cultures of kidney organ-like structures, called kidney organoids.
The findings of EPIORGABOLISM enlighten for the first time the link epigenetic-metabolism in the context of DKD. The action shows that human Embryonic Stem Cell derived kidney organoids cultured in intermittent hyperglycaemia condition can recapitulate important functional and structural characteristic of DKD. Moreover, the intermittent glucose model developed in EPIORGABOLISM can offer improved insight into the mechanism underlying the metabolic memory in DKD. We found that changes in TET1 expression in tubular renal cells from hESC kidney organoids and patients might suggest a link between metabolic changes and DNA methylation. Thus, our model may also serve as a tool for drug discovery to identify therapeutic targets for DKD.
