Table 2.
Summary of the mediators for extraglomerular crosstalk in DKD.
| Crosstalk | Ligand/Receptor | Extracellular vesicles | Signal pathway | Pathological role in DKD | Reference |
|---|---|---|---|---|---|
| Podocyte-Tubular epithelial cell | miR-6538, miR-3474, miR-1981-3p, miR-7224-3p. Let-7f-2-3p | Upregulation of Let-7f-2-3p and downregulation of miR-1981-3p, miR-3474, miR-7224-3p and miR-6538 were detected by RT-qPCR in DKD. These EVs from podocyte may travel through the urinary tract and involved in the extrinsic apoptotic signaling pathway of TECs. | (88) | ||
| miR-221 | Podocyte-derived EVs in diabetes acted as key mediators of proximal tubule cell injury and the miR-221 in EVs mediated the cells damage through Wnt/β-catenin signaling. | (103) | |||
| Tubular epithelial cell-Podocyte | Sirt1 | Sirt1 in tubular epithelial cell protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function. | (102) | ||
| SGLT2-NaCl | Glomerular hyperfiltration is proposed to be resulted from tubular growth and upregulates sodium-glucose cotransporter 2 (SGLT2), which enhances proximal tubular reabsorption, leading a reduction of sodium chloride (NaCl) delivery to the macula densa, therefore increasing GFR via TGF response. | (99–101) | |||
| Macrophage-Podocyte | miR-21-5p | EVs miR-21-5p secreted from macrophage through inhibition of A20 elevate the inflammasome NLRP3, caspases-1 and IL-1β related to pyroptosis, and augment the production of ROS, thereby causing podocyte injury. | (104) | ||
| Tubular epithelial cell- Macrophage | miR-19b-3p | Exosomes enriched with miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation and tubulointerstitial inflammation though SOCS-1 pathway. | (105) | ||
| Intercalated cell-Principle cell | Notch2-Hes1 | Genes encoding Notch ligands were highly expressed in ICs while Notch2 receptor and its transcriptional target Hes1 were shown in PCs with high expression level, suggesting that PCs are the Notch signal-receiving cells in the collecting duct. | (3) |
DKD, diabetic kidney disease; TEC, Tubular epithelial cell; RT-qPCR, real-time polymerase chain reaction; EVs, Extracellular vesicles; IL-1β, Interleukin 1β; ROS, Reactive oxygen species; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; SOCS-1, Suppressor of cytokine signaling-1; Sirt1, Silencing information regulator 2 related enzyme 1; NMN, nicotinamide mononucleotide; SGLT2, sodium-glucose cotransporter 2; NaCl, sodium chloride; Hes1, Hairy and enhancer of split homolog-1; PCs, principle cells; ICs, principle cell.