Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.
Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.
Kelly
Darren J
DJ
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Gilbert
Richard E
RE
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Cox
Alison J
AJ
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Soulis
Tina
T
Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia.
Jerums
George
G
Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia.
Cooper
Mark E
ME
Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia.
D000818:Animals; D001345:Autoradiography; D003094:Collagen / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006133:Growth Substances / Q000378:metabolism / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000503:physiopathology; D008297:Male; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D017127:Glycation End Products, Advanced; D006133:Growth Substances; D006146:Guanidines; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; C004479:pimagedine