The Influence of Hydroxyl Group on Nerve Excitability Blockade by Limonene and Its Hydroxylated Metabolites, Perillyl Alcohol and Carveol.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus, and has become the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. Approximately 40% of individuals with diabetes develop DKD during their lifetime (). The pathogenesis of DKD involves multiple factors, including metabolic disorders, oxidative stress, inflammation, and fibrosis. DKD has long been regarded as a predominantly glomerular disease, and earlier studies have focused primarily on glomerular basement membrane thickening, mesangial matrix expansion, and podocyte injury and glomerulosclerosis. However, renal tubular epithelial cells (RTEC) are the main functional cells of the kidney, responsible for reabsorption and secretion, and their dysfunction directly leads to renal function decline. Recent studies in recent years have shown that RTECs exhibit dysfunction in early-stage DKD, and tubular injury correlates more strongly with renal function decline than glomerulopathy does, with a correlation coefficient of r = 0.67 (). Mitochondria, the cellular “powerhouse”, are particularly abundant in RTECs to sustain their high-capacity reabsorptive function. In DKD, metabolic stress such as high glucose and high fat induces mitochondrial dysfunction, which in turn elicits adaptive metabolic alterations, a process termed “mitochondrial metabolic reprogramming” (). Metabolic reprogramming is characterized by impaired oxidative phosphorylation (OXPHOS), enhanced glycolysis, impaired fatty acid oxidation (FAO), and abnormal lipid accumulation in RTECs, ultimately leading to oxidative stress, inflammation, and apoptosis (). At the same time, the role of epigenetic modifications in the pathogenesis of DKD has attracted increasing attention. DNA methylation, histone modification, and noncoding RNA regulation can persistently affect gene expression by altering chromatin structure and gene accessibility without changing the DNA sequence (). Notably, metabolic reprogramming and epigenetic modification are not two isolated pathological processes but form a complex regulatory network. Metabolic intermediates are directly involved in the activity regulation of epigenetic modifying enzymes, while epigenetic mechanisms affect metabolic status by regulating the expression feedback of metabolic genes, forming a complex bidirectional regulatory network (, ).