Table 1.
Tubule-derived factors regulating myofibroblast activation
| Profibrotic factor | Main effects | Ref. |
|---|---|---|
| TGF-β | TGF-β (1) directly triggers ECM synthesis via Smad3-dependent or independent manners, (2) suppresses the ECM degradation by inhibiting MMPs and inducing natural inhibitors of MMPs (like TIMPs), (3) induces trans-differentiation of myofibroblasts, and (4) mesangial cells proliferation and elimination of TECs, podocytes, and endothelial cells | 22–31,273–276 |
| HER2 | Tubule-derived HER2 induces the profibrotic CTGF expression via activating STAT3 | 277 |
| FGF2 | Autophagy-mediated expression and secretion of FGF2 activates fibroblasts | 278,279 |
| Wnt | Epithelial-derived Wnt ligands induce fibroblasts proliferation and differentiation into myofibroblasts | 68,69 |
| Hh | Hh promotes the transcription factor Glis nuclear translocation, and Shh upregulates the expression of Snail, α-SMA, fibronectin, and collagen I in fibroblasts | 75,280 |
| PDGFs | PDGFs mediate the proliferation, migration, and activation of mesangial cells, fibroblasts, and vascular smooth-muscle cells | 22,281 |
| CTGF | CTGF (1) is a co-factor for TGF-β, (2) activates the Wnt signaling pathway via interacting with LRP6, and (3) induces the trans-differentiation of pericytes and fibroblasts into myofibroblasts | 282–284 |
| TIMP | Timp1 promotes fibroblast proliferation | 285 |
| Lcn2 | Lcn2 increases collagen production in tubular cells | 286 |
| INHBB | INHBB promotes interstitial fibroblast activation through the release of profibrotic activin B from the injured TECs | 83 |
| Connexin 43 | Cx43 mediates the ATP release from TECs, inducing the release of CXCL10 from peritubular macrophage and activation of intrarenal fibroblasts | 287 |
| DACH1 | DACH1 controls the expression of cell cycle and myeloid chemotactic factors (e.g., CSF1, CCL2), contributing to macrophage infiltration and fibrosis development. | 288 |
α-SMA alpha-smooth-muscle actin, ATP adenosine triphosphate, CCL2 chemokine (C-C motif) ligand 2, CSF1 colony-stimulating factor 1, CTGF connective tissue growth factor, CXCL10 C-X-C motif chemokine ligand 10, Cx43 Connexin 43, DACH1 Dachshund homolog 1, ECM extracellular matrix, FGF2 fibroblast growth factor 2, HER2 human epidermal growth factor receptor 2, Hh hedgehog, INHBB inhibin subunit beta B, Lcn2 lipocalin, LRP6 low-density lipoprotein receptor-related protein 6, MMP matrix metallopeptidase, PDGF platelet-derived growth factor, Shh Sonic hedgehog, STAT3 signal transducer and activator of transcription 3, TEC tubular epithelial cell, TGF-β transforming growth factor-b, TIMP tissue inhibitor of matrix metalloproteinase 1