A Purpose-Synthesised Anti-Fibrotic Agent Attenuates Experimental Kidney Diseases in the Rat

Abstract

Background and PurposeLocally-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-ß (TGF-ß) 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-ß 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 ApproachAccordingly, 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 ResultsIn the in vitro setting, FT011 inhibited both TGF-ß1 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 ImplicationsTogether these studies suggest that broadly antagonising growth factor actions, including those of TGF-ß1 and PDGF-BB, has the potential to protect the kidney from progressive injury in both the diabetic and non-diabetic settings.

New renal drug development to face chronic renal disease

“…4.1 Beyond the line: revert fibrosis and its functional relevance in drug discovery Takakuta's pivotal paper on renoprotective properties of the antifibrotic agent pirfenidone [137] showed that delay of fibrosis improves kidney function in the subtotally nephrectomized rat model and was recently corroborated by an independent study using a totally different antifibrotic compound, the small-molecule antifibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia) [138]. In human, a similar pirfenidone renoprotective effect was observed in patients with diabetic nephropathy [139] and with focal segmental glomerulosclerosis [140], slowing the loss of GFR.…”

Therapeutic targets for treating fibrotic kidney diseases

“…FT011 and FT061 are orally-active analogs that have been demonstrated to attenuate TGF-β1-stimulated collagen production in cultured renal mesangial cells and reduce albuminuria in rodent models of progressive diabetic nephropathy. 52,53 In addition to inhibiting TGF-β1-induced collagen production, FT011 was found to also inhibit the pro-fibrotic and pro-proliferative effects of platelet-derived growth factor (PDGF) and significantly reduced renal fibrosis and interstitial macrophage infiltration and attenuated the decline in renal function. 53 FT011 (Fibrotech Therapeutics, Melbourne, Australia) is currently in clinical development for the treatment of diabetic nephropathy.…”

Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

“…No significant difference in systolic blood pressure was found between treated and untreated diabetic rats and between treated and untreated controls. These data have been previously described [5].…”

“…Control and diabetic model animals were then randomised to two groups each (n010), receiving treatment with either FT011 (200 mgkg −1 day −1 ; Fibrotech Therapeutics, Melbourne, VIC, Australia) or vehicle (1% carboxymethyl cellulose) by gavage for 16 weeks [5]. Blood glucose and blood pressure were measured as previously described [5]; the kidney tissues used in this study were taken from these animals.…”

“…We recently identified a new anti-fibrotic agent called FT011 that attenuated fibrosis in experimental diabetic cardiomyopathy and nephropathy [5,6]. Investigation of the action of FT011 on the diabetic kidney resulted in the observation that Armanni-Ebstein lesions were absent.…”