Mechanisms of metabolic memory and renal hypoxia as a therapeutic target in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is a worldwide public health problem. The definition of DKD is under discussion. Although the term DKD was originally defined as 'kidney disease specific to diabetes,' DKD frequently means chronic kidney disease with diabetes mellitus and includes not only classical diabetic nephropathy, but also kidney dysfunction as a result of nephrosclerosis and other causes. Metabolic memory plays a crucial role in the progression of various complications of diabetes, including DKD. The mechanisms of metabolic memory in DKD are supposed to include advanced glycation end-products, deoxyribonucleic acid methylation, histone modifications and non-coding ribonucleic acid including micro ribonucleic acid. Regardless of the presence of diabetes mellitus, the final common pathway in chronic kidney disease is chronic kidney hypoxia, which influences epigenetic processes, including deoxyribonucleic acid methylation, histone modification, and conformational changes in micro ribonucleic acid and chromatin. Therefore, hypoxia and oxidative stress are appropriate targets of therapies against DKD. Prolyl hydroxylase domain inhibitor enhances the defensive mechanisms against hypoxia. Bardoxolone methyl protects against oxidative stress, and can even reverse impaired renal function; a phase 2 trial with considerable attention to heart complications is currently ongoing in Japan.

Keywords: Diabetic kidney disease; Metabolic memory; Renal hypoxia.

Figure 1

A Venn diagram of the notions of diabetic kidney disease and diabetic nephropathy. Diabetic nephropathy, which was originally a pathological diagnosis, includes only patients or animals whose kidney damage was obviously from diabetes mellitus. In contrast, diabetic kidney disease means chronic kidney disease with diabetes, regardless of other comorbidities, such as atherosclerosis and glomerulonephritis. Therefore, diabetic kidney disease encompasses diabetic nephropathy.

Figure 2

Regulation of hypoxia‐inducible factor (HIF) and NF‐E2‐related factor 2 (Nrf2). (a) Regulation of HIF. HIF‐α undergoes hydroxylation by prolyl hydroxylase domain (PHD) in a normoxic condition, resulting in proteasomal degradation. Under hypoxia or PHD inhibition, HIF‐α is not hydroxylated, but is stabilized in cytosol and forms a heterodimer with HIF‐β. This heterodimer translocates into the nucleus, binds to the consensus enhancer through hypoxia‐responsive elements and activates downstream genes. (b) Regulation of Nrf2. Nrf2 is recognized by Kelch‐like ECH‐associated protein 1 (KEAP1) under non‐stressful conditions, followed by proteasomal degradation. Under a stressful condition of pharmaceutical KEAP1 inhibition, Nrf2 cannot be recognized by KEAP1, and is stabilized in the cytosol. Increased concentration of Nrf2 results in nuclear translocation, binding to the consensus enhancer through anti‐oxidant‐responsive elements, and activation of downstream genes.