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.

The mechanisms underlying the therapeutic effect of Salvia miltiorrhiza (SM) on diabetic nephropathy (DN) were examined using a systematic network pharmacology approach and molecular docking. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredients of SM. Targets were obtained using the SwissTargetPrediction and TCMSP databases. Proteins related to DN were retrieved from the GeneCards and DisGeNET databases. A protein–protein interaction (PPI) network was constructed using common SM/DN targets in the STRING database. The Metascape platform was used for GO function analysis, and the Cytoscape plug-in ClueGO was used for KEGG pathway enrichment analysis. Molecular docking was performed using iGEMDOCK and AutoDock Vina software. Pymol and LigPlos were used for network mapping. Sixty-six active ingredients and 189 targets of SM were found. Sixty-four targets overlapped with DN-related proteins. The PPI network revealed that AKT1, VEGFA, IL6, TNF, MAPK1, TP53, EGFR, STAT3, MAPK14, and JUN were the 10 most relevant targets. Go and KEGG analyses revealed that the common targets of DN and SM were mainly involved in advanced glycation end products, oxidative stress, inflammatory response, and immune regulation. Molecular docking revealed that potential DN-related targets, includingTNF, NOS2, and AKT1, more stably bound with salvianolic acid B than with tanshinone IIA. In conclusion, this study revealed the active components and potential molecular therapeutic mechanisms of SM in DN and provides a reference for the wide application of SM in clinically managing DN.

Diabetic nephropathy (DN) is not only an important microvascular complication of diabetes but also the main cause of end-stage renal disease. Studies have shown that the occurrence and development of DN are closely related to morphological and functional changes in podocytes. A series of morphological changes after podocyte injury in DN mainly include podocyte hypertrophy, podocyte epithelial-mesenchymal transdifferentiation, podocyte detachment, and podocyte apoptosis; functional changes mainly involve podocyte autophagy. More and more studies have shown that multiple signaling pathways play important roles in the progression of podocyte injury in DN. Here, we review research progress on the pathological mechanism of morphological and functional changes in podocytes associated with DN, to provide a new target for delaying the occurrence and development of this disorder.

Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.

Diabetic kidney disease (DKD) is one of the major complications of diabetes, and its pathological progression is closely associated with lipid metabolic reprogramming. Under diabetic conditions, renal cells undergo significant lipid metabolic abnormalities, including increased lipid uptake, impaired fatty acid oxidation, disrupted cholesterol efflux, and enhanced lipid catabolism, as adaptive responses to metabolic stress. These changes result in the accumulation of lipids such as free fatty acids, diacylglycerol, and ceramides, leading to lipotoxicity that triggers inflammation and fibrosis. Hypoxia in the DKD microenvironment suppresses fatty acid oxidation and promotes lipid synthesis through the HIF-1α pathway, while chronic inflammation exacerbates lipid metabolic disturbances via inflammatory cytokines, inflammasomes, and macrophage polarization. Targeting lipid metabolism represents a promising therapeutic strategy for alleviating DKD; however, further clinical translational studies are warranted to validate the efficacy and safety of these approaches.

Diabetic kidney disease (DKD), a severe and long-term complication of diabetes, is a microcirculatory pathology influenced by diabetes-related factors that affects hundreds of millions of people worldwide. DKD is characterized by proteinuria, glomerular injury, and renal fibrosis, ultimately leading to end-stage renal disease. Its pathogenesis is complex and involves multiple cellular and molecular mechanisms. Microcirculatory disorders form the fundamental pathological basis of DKD. These disorders are primarily manifested through changes in the number and structure of renal microvessels, alterations in renal hemodynamics, formation of renal thrombi, glomerular endothelial cell dysfunction, and associated lesions in podocytes and mesangial cells. This article focuses on renal microangiopathy and glomerular endothelial cell (GEC) dysfunction, summarizing the mechanisms associated with microcirculatory lesions in DKD, including nitric oxide (NO), advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), the renin-angiotensin-aldosterone system (RAAS), reactive oxygen species (ROS), the NLRP3 inflammasome, protein kinase C (PKC), epidermal growth factor receptor (EGFR), and platelet-derived growth factor (PDGF). Additionally, we briefly introduce the characteristics of DKD animal models in terms of renal microcirculation and discuss the application of relevant technological tools in studying microcirculatory lesions in DKD.