Table 1.
Summary of the mediators for intraglomerular crosstalk in DKD.
| Crosstalk | Ligand/Receptor | Extracellular vesicles | Signal pathway | Pathological role in DKD | Reference |
|---|---|---|---|---|---|
| Podocyte-GEC | VEGFA–VEGFR2 | The expression of VEGFA and VEGFR2 is increased in early DKD, but with the loss of podocytes at later stage of DKD, the expression of VEGFA is also significantly decreased. The VEGFA-VEGFR2 signaling contribute to vascular rarefication and renal fibrosis in the development of DKD. | (3, 60–63, 91) | ||
| Angpt1/2–Tie2 | Decreased ratio of Angpt-1/Angpt-2 contributes to the development of DKD. Angpt-1 could retard the development of albuminuria as well as glomerular endothelial cell proliferation, whereas Angpt-2 has the opposite effects in DKD. | (3, 64) | |||
| Edn-1–EdnRA | The expression of Edn-1 is upregulated in DKD and combined with the receptor EdnRA, which contributes to the mitochondrial dysfunction of endothelial cell and podocyte apoptosis. | (64, 66–69) | |||
| SDF-1–CXCR4 | SDF-1/CXCR4 axis is involved in the pathogenesis of glomerulosclerosis in case of type 2 diabetes. Inhibition of SDF-1significantly reduced diffuse glomerulosclerosis and prevented albuminuria in the diabetic model. | (70) | |||
| ANGPTL4 | An upregulation of podocyte secreted Angptl4 has described in experimental diabetic animal, which contributed to proteinuria and endothelial injury. | (3) | |||
| GEC-Podocyte | APC–PAR1/ EPCR/S1PR1 | A loss of thrombomodulin-dependent protein C activation and aggravated glomerular apoptosis is described in diabetic mice. Increased levels of APC formation prevent podocyte apoptosis and downregulates coagulation and inflammation in DKD. | (72) | ||
| KLF2 | The expression of KLF2 is reduced in diabetic kidneys and it lack aggravates endothelial and podocyte injury in diabetic nephropathy. | (73) | |||
| eNOS | A tight relation has been found between eNOS deficiency and a podocyte-specific injury and heavy albuminuria in advanced DKD. | (75) | |||
| Endothelial glycocalyx | The damage of endothelial glycocalyx and shear-stress is observed in early DKD, and this damage altered organization of extracellular matrix. | (67) | |||
| TGF-β1 | The increased secretion of exosomes enriched with TGF-β1 mRNA probably mediates the EMT and dysfunction of podocytes through the Wnt/β-catenin signaling pathway. | (74) | |||
| Podocyte-PEC | HB-EGF–c-MET | Injured podocytes secrete HB-EGF, which in turn stimulates and promotes the proliferation of PECs while disturbs their compensatory differentiation toward podocytes. | (77, 82) | ||
| IGF–IGFBPs | Dysregulation of the growth hormone/IGF system is found in early DKD and is associated with both glomerular hypertrophy and microalbuminuria. | (82) | |||
| GEC-GMC | PDGFB–PDGFR-β | PDGFR-β signaling is activated in glomeruli and tubule of diabetic mice.It may contribute to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion. | (86, 87) | ||
| TGF-β1 | The increased secretion of exosomes enriched with TGF-β1 mRNA can promote α-SMA expression, proliferation and extracellular matrix protein overproduction in GMCs through the TGFβ1/Smad3 signaling pathway. | (88) | |||
| GMC-GEC | Integrin αvβ8 | The integrin is expressed by mesangial cells, where it sequesters TGF-β, thereby reducing TGF-β signaling. Integrin αvβ8 and its ligand latent TGF-β protect kidney from glomerular dysfunction, endothelial apoptosis, and development of proteinuria, but the role of Integrin αvβ8 in DKD is unknown. | (91) | ||
| Podocyte-GMC | VEGF | The diabetic podocyte produces excessive VEGF in the setting of low endothelial NO and stimulates growth and proliferation of mesangial and endothelial cells, leading to increased extracellular matrix accumulation, hyperfiltration, and proteinuria. | (83) | ||
| GMC-Podocyte | TGF-β1 | Exosomes derived from high-glucose-induced mesangial cells induced podocyte injury through the increased secretion of TGF-β and TGF-β1/PI3K-Akt signaling. | (83, 89) | ||
| ERAD | ERAD-associated genes are downregulated in diabetic Glomeruli, and inhibition of ERAD processes could leading to the suppression of nephrin phosphorylation and podocytes injury under diabetic conditions. | (92) |
DKD, diabetic kidney disease; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; Angpt1/2, angiopoietin-1/2; Tie2, angiopoietin 1 receptor; Edn-1, Endothelin-1; EdnRA, Endothelin receptor A; SDF-1, stromal cell-derived factor 1; CXCR4, C-X-C Chemokine Receptor Type 4; ANGPTL4, angiopoietin-like 4; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; HB-EGF, heparin-binding epidermal growth factor-like growth factor; c-MET, mesenchymal epithelial transition factor; APC, Activated protein C; PAR1, Protease-activated receptor 1; Sirt1, Sirtuin 1; EPCR, endothelial protein C receptor; S1PR1, Sphingosine 1-phosphate receptor 1; TGF-β1, Transforming growth factor β1; KLF2, Krüppel-like factor 2; eNOS, endothelial nitric oxide synthase; PDGFB, Platelet-derived growth factor B; PDGFRβ, platelet-derived growth factor receptor beta; IL-1β, Interleukin 1β; Integrin αvβ8, Integrin alphavbeta8; CCN1, Cellular communication network factor1; INSR, insulin receptors; ERAD, ER-associated protein degradation; NMN, nicotinamide mononucleotide; CCL2, C-C motif chemokine ligand 2; EMT, epithelial-mesenchymal transition; α-SMA, α-smooth muscle actin; GMC, glomerular mesangial cell; GEC, glomerular endothelial cell; PEC, parietal epithelial cell.