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.

Fig. 1

Pathological structural changes of glomerular cells in DKD. Healthy glomeruli includes glomerular endothelial cells, parietal cells, basement membrane, podocytes, podocyte foot process and MCs; The glomerular manifestations of DKD include podocyte foot process effacement, basement membrane thickening, podocyte hypertrophy, podocyte apoptosis, apoptosis of GECs and mesangial expansion

Fig. 2

The available evidence to summarize the early to late periods of intracellular cell interactions in the glomerulus. During the progression of DKD, the mechanisms of intracellular cell interactions in the glomerulus at different stages have different emphases. In the early stage of DKD, there is a tendency towards loss of podocytes and angiogenesis disorders, and the glomerular filtration barrier begins to be damaged. With more ROS being produced, the progression of DKD develops further. In the transitional period, mesangial expansion and sclerosis accompanied by overproduction of ECM, gradually lead to renal fibrosis and ultimately develop into the late-stage of DKD. The over-activation of a series of renal fibrotic pathways with TGFΒ as the core and the release of exosomes of related signal transmitters eventually aggravate the renal fibrotic process of DKD, resulting in a sharp decline in renal function and developing into the end-stage renal disease