Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives

Abstract

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized the role of renal tubular injury in the pathogenesis of DKD. Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER stress, inflammation, EMT and programmed cell death, have been shown to induce renal tubular injury and contribute to the progression of DKD. Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence therapies, mineralocorticoid receptor antagonists, and stem cell therapies have demonstrated their potential to alleviate renal tubular injury in DKD. This review will provide insights into the latest research on the mechanisms and treatments of renal tubular injury in DKD.

Unleashing the pathological role of epithelial-to-mesenchymal transition in diabetic nephropathy: The intricate connection with multifaceted mechanism

“…EMT plays a crucial role in the development and progression of diabetic nephropathy, a common and devastating consequence of diabetes mellitus that can lead to end-stage renal disease[ 5 ]. EMT primarily affects renal tubular epithelial cells in diabetic nephropathy, resulting in renal fibrosis, inflammation, and, eventually, kidney function loss[ 6 , 7 ].…”

“…These alterations promote the accumulation of myofibroblasts and ECM deposition, resulting in renal interstitial fibrosis. Hyperglycemia and metabolic abnormalities in the diabetic kidney activate signaling pathways such as transforming growth factor-beta (TGF-β) and Wnt/β-catenin, which are known to trigger EMT[ 7 ]. This process transforms renal tubular epithelial cells into myofibroblasts, which release ECM components and contribute to progressive fibrosis in diabetic kidney disease[ 7 ].…”

Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection

“…The specific molecular mechanisms, contributing to DKD in about one-third of patients with diabetes, are still unclear [3]. Although previous studies were historically focused on glomerular damage, there is increasing literature on the role of tubular injury in the pathogenesis of DKD [4]. Glomerular hyperfiltration and alterations of the extracellular matrix lead to mesangial matrix expansion and increased thickness of the glomerular basement membrane (GBM) [3].…”

“…The degree of podocyte damage and glomerulosclerosis correlates closely with albuminuria and the decline of renal function [3]. However, the rate of kidney function loss is more closely related to tubular damage and interstitial fibrosis than to glomerular damage [4]. Apart from this distinction between the two sites of renal damage, the onset of DKD involves different pathways, which are broadly classifiable into metabolic, oxidative, inflammatory, fibrotic, and hemodynamic [5].…”

Integrated Network Pharmacology Analysis and Experimental Validation to Elucidate the Mechanism of Acteoside in Treating Diabetic Kidney Disease

“…34,35 Pyroptosis, characterized as a pro-inflammatory programmed cell death, compounds renal dysfunction and intensifies renal fibrosis, highlighting its significance in DKD pathophysiology. 36 NF-κB is essential to pyroptotic mediation, catalyzing NLRP3 protein oligomerization and subsequent inflammasome assembly, and subsequently activating Caspase1. Caspase1 mediates the cleavage of the Gasdermin D (GSDMD) protein, forming pores on the cellular membrane.…”