Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy.
OBJECTIVE
Tubulointerstitial pathology with the accumulation of extracellular matrix are pathological hallmarks of diabetic nephropathy that are directly related to declining renal function. Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid), an inhibitor of transforming growth factor-beta (TGF-beta), used to treat hypertrophic scars has recently been shown in pilot studies to exert a beneficial effect in advanced diabetic nephropathy in humans. However, its effects on diabetic renal pathology are unknown.


METHODS
Studies were conducted using a transgenic model, the diabetic (mRen-2)27 rat, which develops many of the structural and functional characteristics of human diabetic nephropathy when diabetes is induced with streptozotocin (STZ). An experimental design was chosen to mimic, in part, the clinical context with drug therapy (tranilast 400 mg/kg/ day) initiated in established disease (8 weeks after STZ) and in the presence of persistent hyperglycaemia and hypertension.


RESULTS
At 16 weeks, diabetes was associated with progressive albuminuria, tubulointerstitial fibrosis and tubular atrophy. Without affecting blood pressure or blood glucose, tranilast treatment was associated with a 83% reduction in tubulointerstitial fibrosis (p < 0.001), a 58% reduction in tubular atrophy (p < 0.01) and near normalization of albuminuria (p < 0.05) in diabetic Ren-2 rats. In vitro studies in primary cultures of human renal cortical fibroblasts demonstrated a reduction in TGF-beta-induced hydroxyproline incorporation and fibronectin synthesis with tranilast 100 microM.


CONCLUSIONS
Tranilast, when administered during the course of experimental diabetic nephropathy, attenuates tubulointerstitial pathology and albuminuria. These findings are consistent with the antagonist effects of tranilast on TGF-beta actions in the diabetic kidney.
Mifsud
Sally
S
Department of Physiology, University of Melbourne and St. Vincent's Hospital, Melbourne, Vic., Australia.
Kelly
Darren J
DJ
Qi
Weier
W
Zhang
Yuan
Y
Pollock
Carol A
CA
Wilkinson-Berka
Jennifer L
JL
Gilbert
Richard E
RE
D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D030801:Animals, Genetically Modified; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001284:Atrophy; D015153:Blotting, Western; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011392:Proline / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014316:Tritium; D062367:ortho-Aminobenzoates / Q000494:pharmacology* / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D024141:Collagen Type IV; D005353:Fibronectins; C473112:Ren2 protein, mouse; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D014316:Tritium; D011392:Proline; D012083:Renin; C012293:tranilast