Epigenetic alterations and memory: key players in the development/progression of chronic kidney disease promoted by acute kidney injury and diabetes

Chronic kidney disease (CKD) is a highly prevalent global public health issue and can progress to renal failure. Survivors of acute kidney injury (AKI) have an increased risk of progressing to CKD by 8.8-fold and kidney failure by 3.1-fold. Further, 20%‒40% of individuals with diabetes will develop CKD, also known as diabetic kidney disease (DKD). Thus, preventing these kidney diseases can positively impact quality-of-life and life-expectancy outcomes for affected individuals. Frequent episodes of hyperglycemia and renal hypoxia are implicated in the pathophysiology of CKD. Prior periods of hyperglycemia/uncontrolled diabetes can result in development/progression of DKD even after achieving normoglycemia, a phenomenon known as metabolic memory or legacy effect. Similarly, in AKI, hypoxic memory is stored in renal cells even after recovery from the initial AKI episode and can transition to CKD. Epigenetic mechanisms involving DNA methylation, chromatin histone post-translational modifications and non-coding RNAs are implicated in both metabolic and hypoxic memory, collectively known as "epigenetic memory." This epigenetic memory is generally reversible and provides a therapeutic avenue to ameliorate persistent disease progression due to hyperglycemia and hypoxia and prevent/ameliorate CKD progression. Indeed, therapeutic strategies targeting epigenetic memory are effective at preventing CKD development/progression in experimental models of AKI and DKD. Here, we review the latest in-depth evidence for epigenetic features in DKD and AKI, and in epigenetic memories of AKI-to-CKD transition or DKD development and progression, followed by translational and clinical implications of these epigenetic changes for the treatment of these widespread kidney disorders.