Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model.
Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-beta has been consistently implicated. Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-beta-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 (x)/(/) 1.2 versus 20.5 (x)/(/) 1.3 mg/d; P < 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P < 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-beta activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-beta signaling in vivo. In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.
Kelly
Darren J
DJ
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia. dkelly@medstv.unimelb.edu.au
Zhang
Yuan
Y
Gow
Renae
R
Gilbert
Richard E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects*; D018076:DNA, Complementary / Q000032:analysis; D004195:Disease Models, Animal; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology* / Q000517:prevention & control; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007683:Kidney Tubular Necrosis, Acute / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D008969:Molecular Sequence Data; D009392:Nephrectomy; D009924:Organ Culture Techniques; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D018076:DNA, Complementary; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; C012293:tranilast