Table 3.
Studies reporting in vivo effects of imatinib.
| Model of Renal Fibrosis | Intervention | Main Reported Effects on Renal Fibrosis | Ref |
|---|---|---|---|
| Mesangial proliferative (anti-Thy-1) glomerulonephritis (Wistar rats) |
50 mg/kg; daily by intraperitoneal injections, for 6 days |
- Imatinib ameliorated glomerular hypercellularity; - reduced mesangial cell proliferation (ED-1 and BrdU double IHC); - reduced activation of mesangial cells (α-SMA IHC) and type IV collagen deposition; - no effect on glomerular macrophage infiltration and proliferation. |
[83] |
| Chronic allograft nephropathy (allografts from Dark Agouti to Wistar-Furth rats) |
10 mg/kg; daily by oral gavage for 5 or 90 days |
- Imatinib inhibited the development of fibrosis associated with chronic allograft nephropathy (Masson trichrome staining); - reduced protein expression of ligands PDGFA and PDGFB, and receptors PDGFRα and PDGFRβ; - inhibited infiltration of macrophages and CD4+ T cells into the grafts. |
[84] |
| Diabetic nephropathy (C57BL6 apolipoprotein E–knockout mice) |
10 mg/kg; daily by oral gavage for 20 weeks |
- Imatinib reduced glomerular injury (attenuated increased glomerular size and mesangial area) and tubulointerstitial area; - prevented the increase in α-SMA–positive cell expression in the glomeruli and in the tubulointerstitium in diabetic mice; - reduced accumulation of collagen type I and type IV; - reduced expression of Ki-67–positive cells; - reduced PDGFB protein and gene expression; - reduced PDGFRβ gene expression; - reduced TGFβ1 protein expression, but not gene expression; - reduced CTGF protein and gene expression; - decreased macrophage infiltration. |
[72] |
| Lupus nephritis (MRL/lpr mice) |
10 mg/kg or 50 mg/kg; daily by oral gavage 4 times per week up to 8 weeks |
Imatinib at 50 mg/kg: - ameliorated glomerulonephritis (reduced proliferation of glomerular cells, infiltrating inflammatory cells and reduced mesangial matrix); - reduced proportional area of glomeruli staining positive for PDGFRβ; - reduced expression mRNA levels of PDGFRβ and TGFβ1. - Treatment with 10 mg/kg imatinib did not affect PDGF signaling, and thus failed to ameliorate the nephritis. |
[85] |
| Lupus nephritis (New Zealand Black/White (NZB/W) F1 hybrid mice) |
50 mg/kg; twice a day by oral gavage for 3 months (or longer for survival studies) |
- Imatinib limited glomerular hypercellularity, IgG deposits, and tubulointerstitial damage; - reduced interstitial expression of α-SMA in fibroblasts; - reduced mRNA expression of TGFβ1; - reduced infiltrates of monocytes/macrophages. |
[86] |
| Cryoglobulinemic MPGN (TSLP-transgenic mice) |
50 mg/kg; daily by intraperitoneal injection for 2, 4 or 8 weeks |
- Imatinib decreased accumulation of collagen IV; - reduced mesangial cell activation (measured by % GTA occupied by α-SMA–positive cells); - parenchymal injury and fibrosis were attenuated in a time-dependent manner. - reduced the infiltration of inflammatory cells; - inhibited B cell development; |
[87] |
| Anti-glomerular basement nephritis (Wistar-Kyoto rats) |
50 mg/kg; intraperitoneal injection, from one day before up to 13 days (early treatment) or from day 7 to 20 (late treatment) | - Imatinib reduced glomerular fibrin deposition; - ameliorated glomerular injury (reduced crescents formation and necrosis evaluated by morphological analysis); - attenuated the PDGFRβ mRNA upregulation; - attenuated the c-fms and M-CSF mRNA expression; - reduced glomerular macrophage accumulation, along with an inhibition of IL-1b or MCP-1 expression. |
[75] |
| Anti-glomerular basement nephritis (Wistar-Kyoto rats) |
25 mg/kg; daily by intraperitoneal injection, from day 7 to day 49 (long-term treatment) or from day 7 to 13 (short-term treatment) |
- Imatinib reduced glomerulosclerosis and improved tubulointerstitial damage in rats with NTS nephritis (evaluated by histological analysis); - decreased collagen type I gene expression; - reduced TGFβ1 gene and protein expression. |
[73] |
| UUO model (Sprague-Dawley rats) | dose-accelerating schedule for 7 days (days 1-2: 50 mg/kg; days 3-4: 100 mg/kg; days 5–7: 150 mg/kg), once daily by intraperitoneal injection | - Imatinib blocked TGFβ-stimulated c-abl activity in fibroblasts in obstructed kidneys; - did not block increased PDGFB expression, neither affected increased PAI-1 levels; - reduced proliferation of vimentin-expressing fibroblasts in obstructed kidneys, although induction of α-SMA in fibroblasts was not mitigated; - reduced fibrogenesis, as indicated by reduced accumulation of collagen type III and IV and fibronectin in the renal interstitium; - did not reduce interstitial macrophage infiltration. |
[80] |
| UUO model (C57BL6 wild-type or Coll-GFP mice) | 50 mg/kg; 2h before the surgery, then twice a day until sacrifice on day 4 or 14 |
- Imatinib decreased PDGFRα and PDGFRβ phosphorylation in pericytes in UUO kidneys; - decreased the expanded population of myofibroblasts by inhibiting cell proliferation; - attenuated fibrosis development in UUO kidneys (measured by % Sirius red area); - attenuated macrophage infiltration. |
[88] |
| Unilateral IRI model (C57BL6 wild-type or Coll-GFP mice) | 50 mg/kg; 2h before the surgery, then twice a day until sacrifice on day 4 or 14 |
- Imatinib inhibited pericyte activation and expansion of myofibroblasts in IRI kidneys on days 4 and 14 post IRI; - attenuated interstitial fibrosis on day 14 post IRI (measured by Sirius red staining). |
[88] |
IHC, immunohistochemistry; IgG, immunoglobulin G; MPGN, membranoproliferative glomerulonephritis; TSLP, thymic stromal lymphopoietin; GTA, glomerular tuft area; NTS, nephrotoxic serum; UUO, unilateral ureteral obstruction; IRI, ischemia/reperfusion injury.