Table 2.
Main molecular mediators known to participate in the pathophysiological process of tubular degeneration and interstitial fibrosis, grouped according to their most important effect.
| ENDOGENOUS ACTIVATORS | ORIGIN | FBR & EMT | INF | TD | ISCH | REFERENCES |
|---|---|---|---|---|---|---|
| 1. Fibrosis and EMT | ||||||
| TGF-β | TC, F, MF, P, iG | X | EMT [252,253]; secretion of profibrotic MCP-1 [254] and CTGF [255]. Fibrosis: ↑ECM components and PAI, and ↓MMPs [51,104-106] | |||
| EGF | P, UF | X | EMT [256] | |||
| FGF | P, UF | X | EMT [234]; fibrosis [87,257-259] | |||
| PDGF | P, RC | X | Fibroblast to myofibroblast transformation [87], proliferation of myofibroblasts [260] | |||
| CTGF | TC | X | X | EMT, fibrosis, apoptosis [255,261,262] | ||
| SPARC | TC, F, MF | X | ↓cell adhesion and proliferation, activates TGF-β and collagen I and fibronectin synthesis [98,263] | |||
| Thrombospondin | TC, F, MF | X | Activates TGF-β [99] | |||
| Decorin and biglycan | TC, F, MF | X | Reservoires of bFGF and TGF-β [101,102]. | |||
| Collagen I | F, MF, TC | X | EMT [264] | |||
| PAI-1 | TC, F, MF | X | ECM accumulation and fibrosis [265] | |||
| TIMP-1 | TC, F, MF | X | Fibrosis ? [87,108] | |||
| 2. Inflammation | ||||||
| Complement C3 and C4 | P, TC | X | X | Inflammation and fibrosis [266-269] | ||
| MCP-1 | TC, P, iG | X | X | Cell infiltration, fibrosis [72,74,254] | ||
| ICAM-1 and VCAM-1 | EC, TC | X | On EC: diapedesis and infiltration [270]; On TC: uncertain [271,272] | |||
| Hialuronic acid | TC, F, MF | X | Inflammation, MCP-1 and secretion of adhesion molecules [97,98] | |||
| 3. Tubular damage | ||||||
| Protein overload | UF | X | Tubule cell activation [65] and release of ET-1 [273], ANG-II [274], MCP-1, and RANTES [275] | |||
| Complement C5b-9 | P | X | X | Tubular damage and fibrosis [276] | ||
| TNF-α, IFN-γ, Tweak | iWBC | X | X | X | Inflammation, cell death, fibroblast and myofibroblast activation [277-279] | |
| 4. Ischemia | ||||||
| Endothelin-1 | TC | X | X | Vasoconstriction and ischemia [273,280]; ↑ECM components and TGF-β [87] | ||
| RAS | EC, TC, P | X | Vasoconstriction, ischemia and TGF-β secretion [87,281-284] | |||
| ADMA | Plasma | X | X | Vasoconstriction [67] | ||
| ENDOGENOUS INHIBITORS | ORIGIN | FBR & EMT | INF | TD | ISCH | REFERENCES |
| 1. Fibrosis and EMT | ||||||
| Collagen IV | F, MF, TC | X | Inhibits EMT [285] | |||
| MMP-2 and 9 | TC | X | Degrade collagen IV [286] | |||
| HGF | P | X | Inhibits EMT and fibrosis [287-290] | |||
| BMP-7 | P, TC? | X | Inhibits EMT and fibrosis [285] |
ADMA: asymmetric dimethylarginine; EC: endothelial cells; F: fibroblasts; iG: inflamed glomeruli; iWBC: infiltrated white blood cells; MF: myofibroblasts; P: plasma; RC: renal cells (unspecified); TC: tubular cells; UF: glomerular ultrafiltrate.