A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat.
OBJECTIVE
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.


METHODS
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.


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
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.
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. richard.gilbert@utoronto.ca
Richard E
RE
Gilbert
Yuan
Y
Zhang
Spencer J
SJ
Williams
Steven C
SC
Zammit
David I
DI
Stapleton
Alison J
AJ
Cox
Henry
H
Krum
Robyn
R
Langham
Darren J
DJ
Kelly
D000419:Albuminuria / Q000150:complications / Q000188:drug therapy; D000818:Animals; D000077214:Becaplermin; D002109:Caffeic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects; D053495:Osteopontin / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
C546971:3-methoxy-4-propargyloxycinnamoyl anthranilate; D002109:Caffeic Acids; D020011:Protective Agents; D020574:Proto-Oncogene Proteins c-sis; D053773:Transforming Growth Factor beta1; D062367:ortho-Aminobenzoates; D053495:Osteopontin; D000077214:Becaplermin; D003094:Collagen