Hyperglycaemia-induced molecular reprogramming of proximal tubular epithelial cells and its contribution to diabetic kidney disease progression—a narrative review

Abstract

Diabetic kidney disease (DKD) is the primary contributor to the development of chronic kidney disease and end-stage kidney failure globally. A hyperglycaemic microenvironment is a critical contributor of proximal tubular epithelial cell injury to disease initiation and progression. Hyperglycaemia induces profound molecular, metabolic, and structural alterations in renal tubular epithelial cells, promoting inflammation, fibrosis, and functional decline. Chronic hyperglycaemia activates multiple pathogenic pathways, including the polyol, hexosamine, protein kinase C (PKC), and advanced glycation end-product pathways, resulting in excessive reactive oxygen species generation, mitochondrial dysfunction, inflammation, and extracellular matrix accumulation. Hyperglycaemia also alters the expression of key genes, including biglycan, advanced glycation end products receptor, and BCL2 interacting protein 3, contributing to cellular dysfunction and disease progression. Emerging evidence supports the role of extracellular vesicles, exosomal RNAs, and mitochondrial nucleic acids in mediating tubular injury. Advanced diagnostic platforms, including urinary biomarker panels, proteomics, single-cell RNA sequencing, spatial transcriptomics, and multi-omics approaches, offer improved sensitivity for early detection and mechanistic characterisation of DKD. A hyperglycaemic microenvironment could damage the proximal tubular epithelial cells via mechanisms such as dedifferentiation, metabolic reprogramming, cell death and senescence and other pathways (ENPP1, HIF stabilisation and epigenetic changes). Therefore, these mechanisms are the targets of emerging and novel therapeutic strategies which include HIF-Prolyl Hydroxylase Inhibition, Targeting Maladaptive SOX9+ Cells, Metabolic Targets, Senescence and Senolytics/Senomorphics.