Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Abstract

Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.

Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis

“…DKD is closely associated with the fibrosis of renal tubular epithelial cells [ 73 ], which are epithelial cells located at the outer layer of the renal tubule that act to reabsorb glucose, amino acids, and other substances in the urine [ 74 ]. An earlier study showed that exposure to high glucose or albumin levels can induce renal tubular epithelial cell fibrosis, and this was closely associated with the increased expression of MCP-1, PAI-1, and TGF-β1 as a result of hyperglycemia-induced ROS production [ 75 ]; renal fibrosis can be prevented if these profibrosis genes are suppressed [ 76 ].…”

Transcription Factor ChREBP Mediates High Glucose-Evoked Increase in HIF-1α Content in Epithelial Cells of Renal Proximal Tubules

“…Finally, we were especially interested in the physiological/pathophysiological importance of the high glucose-induced upregulation of HIF-1 in epithelial cells of renal proximal tubules. It is commonly accepted that hypoxia is characteristic of the kidneys of either diabetic patients, as demonstrated due to non-invasive MRI assessment [38], or animal models of the disease [6,39], and it results mainly from increased oxygen consumption, being a consequence of glomerular hyperfiltration and increased activity of sodium-dependent glucose transporters (SGLTs) and Na + /K + ATPase [1,7]. Moreover, hypoxia is one of the factors to be blamed for the development of tubulointerstitial fibrosis, the first step leading to diabetic nephropathy [9,40,41].…”

Harnessing the Full Potential of Multi-Omic Analyses to Advance the Study and Treatment of Chronic Kidney Disease

“…Moreover, harnessing kidney single-cell RNA-seq datasets (160,161), Fan et al deconvolved their dataset to estimate the relative fraction of different kidney cell types within their samples, reporting a significant increase in macrophages, monocytes, fibroblasts, and myofibroblasts in advanced DKD stages, along with a reduction in proximal tubular endothelial cells (158). This transcriptomic analysis reflected results obtained from studies harnessing alternative methods, such as histological examination, which reported increased inflammation and fibrosis during DKD, alongside tubular cell injury (162). Indeed, harnessing single cell RNAseq has rapidly advanced the field of kidney disease research, recently reviewed by Jiang et al (163).…”