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Updated: May 17, 2026
5/6th Nephrectomy in Combination with High Salt Diet and Nitric Oxide Synthase Inhibition to Induce Chronic Kidney Disease in the Lewis Rat
Published on: July 3, 2013
A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat
Richard E Gilbert1, Yuan Zhang, Spencer J Williams
1Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. richard.gilbert@utoronto.ca
Background And Purpose:
Locally-active growth factors have been implicated in the pathogenesis of many diseases in which organ fibrosis is a characteristic feature. In the setting of chronic kidney disease (CKD), two such pro-fibrotic factors, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) have emerged as lead potential targets for intervention. Given the incomplete organ protection afforded by blocking the actions of TGF-β or PDGF individually, we sought to determine whether an agent that inhibited the actions of both may have broader effects in ameliorating the key structural and functional abnormalities of CKD.
Experimental Approach:
Accordingly, we studied the effects of a recently described, small molecule anti-fibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia), which should have these effects.
Key Results:
In the in vitro setting, FT011 inhibited both TGF-β1 and PDGF-BB induced collagen production as well as PDGF-BB-mediated mesangial proliferation. Consistent with these in vitro actions, when studied in a robust model of non-diabetic kidney disease, the 5/6 nephrectomised rat, FT011 attenuated the decline in GFR, proteinuria and glomerulosclerosis (p<0.05 for all). Similarly, in the streptozotocin-diabetic Ren-2 rat, a model of advanced diabetic nephropathy, FT011 reduced albuminuria, glomerulosclerosis and tubulointerstitial fibrosis.
Conclusions And Implications:
Together these studies suggest that broadly antagonising growth factor actions, including those of TGF-β1 and PDGF-BB, has the potential to protect the kidney from progressive injury in both the diabetic and non-diabetic settings.
Insights
A novel drug, FT011, effectively inhibits both transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) in kidney disease models. This dual action protects kidneys from fibrosis and injury in both diabetic and non-diabetic settings.
Area of Science:
- Nephrology
- Pharmacology
- Fibrosis Research
Background:
- Organ fibrosis is a hallmark of many diseases, including chronic kidney disease (CKD).
- Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) are key pro-fibrotic factors implicated in CKD pathogenesis.
- Individual inhibition of TGF-β or PDGF offers incomplete organ protection.
Purpose of the Study:
- To investigate the efficacy of a novel small molecule drug, FT011, in simultaneously inhibiting TGF-β and PDGF.
- To determine if dual inhibition by FT011 provides broader protection against CKD-related structural and functional abnormalities compared to single-target inhibition.
Main Methods:
- In vitro studies assessed FT011's effect on TGF-β1 and PDGF-BB-induced collagen production and PDGF-BB-mediated mesangial proliferation.
- In vivo studies utilized a 5/6 nephrectomized rat model for non-diabetic kidney disease.
- In vivo studies also employed the streptozotocin-diabetic Ren-2 rat model for advanced diabetic nephropathy.
Main Results:
- FT011 inhibited TGF-β1 and PDGF-BB induced collagen production and PDGF-BB-mediated mesangial proliferation in vitro.
- In non-diabetic kidney disease models, FT011 attenuated declines in glomerular filtration rate (GFR), proteinuria, and glomerulosclerosis.
- In diabetic nephropathy models, FT011 reduced albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis.
Conclusions:
- Simultaneous antagonism of growth factors like TGF-β1 and PDGF-BB shows promise for kidney protection.
- FT011 demonstrates potential therapeutic benefits in both diabetic and non-diabetic kidney injury settings.
- Broadly targeting growth factor pathways may be a viable strategy to prevent progressive kidney damage.
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