Crosstalk among podocytes, glomerular endothelial cells and mesangial cells in diabetic kidney disease: an updated review

Abstract

Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria, glomerular damage, and renal fibrosis, leading to end-stage renal disease, and the pathogenesis is complex and involves multiple cellular and molecular mechanisms. Among three kinds of intraglomerular cells including podocytes, glomerular endothelial cells (GECs) and mesangial cells (MCs), the alterations in one cell type can produce changes in the others. The cell-to-cell crosstalk plays a crucial role in maintaining the glomerular filtration barrier (GFB) and homeostasis. In this review, we summarized the recent advances in understanding the pathological changes and interactions of these three types of cells in DKD and then focused on the signaling pathways and factors that mediate the crosstalk, such as angiopoietins, vascular endothelial growth factors, transforming growth factor-β, Krüppel-like factors, retinoic acid receptor response protein 1 and exosomes, etc. Furthermore, we also simply introduce the application of the latest technologies in studying cell interactions within glomerular cells and new promising mediators for cell crosstalk in DKD. In conclusion, this review provides a comprehensive and updated overview of the glomerular crosstalk in DKD and highlights its importance for the development of novel intervention approaches.

Cross-Domain Text Mining of Pathophysiological Processes Associated with Diabetic Kidney Disease

“…The cellular signaling responses include growth factor signaling, the response to nitric oxide, the response to oxidative stress, the cytokine response, macrophage signaling, the TLR pathway, the T-cell-mediated response, NFκB factor activity, ERK/MAPK signaling, the JAK/STAT pathway, the WNT/β-catenin pathway, and NADPH oxidase activity. Several of these pathways are known to be implicated in GEC injury, inflammation, and fibrosis associated with DKD [6,8,11,17]. Similarly, the analyses suggested that the apoptotic processes, the response to cytokines, the T-cell-mediated response, the immune response, calcium channel activity, and growth factor signaling were the most frequent and active biological processes in DKD (Figures 6 and 7).…”

“…The VEGFA gene is central to the regulation of VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2), the adherens junction, nitric oxide, p38/MAPK signaling kinase, and ERK1/ERK2 signaling kinase. Vascular endothelial development and growth in endothelial cells heavily rely on nitric oxide [9,17,42], which is positively influenced by the VEGFA, EGFR, and FCER2 genes and negatively influenced by the the IL-10 protein. RIPK2 and DDX58, as well as GSDMD, RIPK2, and HK1, play positive roles in regulating pro-inflammatory cytokines like IL-6 and IL-1β.…”

“…Previous experimental studies showed that hyperglycemia promotes the imbalance in macrophage phenotypes and chronic glucose exacerbates the regulation of inflammatory responses [12,13]. The dysregulated signaling response leads to progressive kidney damage through loss of glomerular endothelial fenestrations, thickening of the basement membrane, the detachment of podocyte foot processes, mesangial matrix expansion, and glomerular fibrosis [7,[14][15][16][17]. For excellent illustrations of the pathological processes, readers are referred to [7,8,16,17].…”

“…The dysregulated signaling response leads to progressive kidney damage through loss of glomerular endothelial fenestrations, thickening of the basement membrane, the detachment of podocyte foot processes, mesangial matrix expansion, and glomerular fibrosis [7,[14][15][16][17]. For excellent illustrations of the pathological processes, readers are referred to [7,8,16,17].…”

Exosomes derived from mesenchymal stem cells in diabetes and diabetic complications

“…Podocytes, which are specialized epithelial cells located in the glomerulus, are an important part to maintain the charge barrier function together with vascular endothelial cells (ECs) [ 56 ]. Research has indicated that hyperglycemia has the potential to induce podocyte apoptosis, resulting in proteinuria, with or without loss of renal function owing to glomerulosclerosis [ 57 ].…”