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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 18, 2003 as doi:10.1096/fj.02-1102fje. |
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* Division of Diabetic Complications, Baker Medical Research Institute, Melbourne, Australia;
Alteon Inc., Ramsey, New Jersey, USA; and
Department of Endocrinology, Austin and Repatriation Medical Centre, Heidelberg, Australia
2Correspondence: Division of Diabetic Complications, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Victoria, 8008 Australia. E-mail: Josephine.forbes{at}baker.edu.au
SPECIFIC AIMS
The aim of this study was to investigate the hypothesis that renal injury in diabetes is partly mediated by AGEs and that the cross-link breaker ALT-711 as a delayed intervention, once early renal injury is evident, is capable of improving renal structure and function. The potential molecular mediators of AGE-induced renal injury were assessed, including TGF-ß, CTGF, as well as expression of collagens.
PRINCIPAL FINDINGS
1. Systolic blood pressure was increased in diabetic animals compared with controls (C) (P<0.001 vs. C)
Onset of treatment with ALT-711 either late after 24 wk of diabetes (DALT late) or early after 16 wk of diabetes (DALT early) was associated with a decrease in blood pressure (DALT early, wk 16 vs. wk 24, P<0.01; DALT late, wk 24 vs. wk 32, P<0.01) resulting in lower blood pressures for the treated groups when compared with untreated diabetic rats at 32 wk (P<0.01, DALT late vs. D; P<0.05, DALT early vs. D).
2. Twenty-four hour albumin excretion rate (AER) increased over time in the diabetic (D) group (P<0.001 vs. C, Fig. 1
A) and was attenuated with ALT-711 treatment for either duration (P<0.001 D vs. DALT early, P<0.001 D vs. DALT late)
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3. Serum AGE peptide levels increased over time in the diabetic group (P<0.001 vs. control, Fig. 1B
)
This was attenuated at 24 wk in the DALT early group (P<0.001 vs. D). By wk 32 serum AGE peptide levels in both DALT groups were significantly lower than in the untreated diabetic group (P<0.001 vs. D).
4. Tail tendon collagen solubility was reduced by diabetes (P<0.001 vs. C) and early treatment with ALT-711 was effective in restoring collagen solubility to control levels (P<0.001 vs. D)
Tail collagen solubility in the DALT late group was intermediate between untreated and early ALT-711-treated diabetic groups.
5. Immunostaining for the nonfluorescent AGE carboxymethyllysine (P<0.001 vs. C) revealed a diabetes-induced increase, which was attenuated by both ALT-711 treatments irrespective of duration of treatment (P<0.001 vs. D)
6. Staining for RAGE showed a similar pattern to CML, and was increased in diabetic animals (P<0.001 vs. C) and reduced in both diabetic ALT-711 treatment groups (P<0.01 vs. D)
7. Renal transforming growth factor ß1 gene (P<0.001 vs. C) and protein expression (Fig. 2A-D
, P<0.001 vs. C) were increased in diabetic animals diabetes and only ameliorated by early intervention with ALT-711
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8. CTGF gene expression was significantly increased in the diabetic kidney (P<0.001 vs. D).
Both the DALT early and DALT late groups showed attenuation of CTGF gene expression (P<0.001 vs. D)
9. Diabetes induced a significant increase in both gene (P<0.001) and protein expression of collagen IV (P<0.001 vs. C); this increase in the diabetic animals was only reduced significantly by early intervention with ALT-711 (P<0.001 vs. D)
10. Glomerulosclerotic index (P<0.001 vs. C) and tubulointerstitial area (P<0.001 vs. C) were both significantly increased in the diabetic group
The DALT early group demonstrated an attenuation of this increase in TIA and GSI. However, there was no attenuation of either of these two parameters of renal structural injury in the DALT late group.
11. Diabetes induced increases in renal cortical nitrotyrosine levels that were attenuated by early intervention with ALT-711 (P<0.0001 vs. D)
Nitrotyrosine was reduced to a lesser degree by late intervention with ALT-711 (P<0.0005 DALT late vs. D).
CONCLUSIONS AND SIGNIFICANCE
This study has provided further evidence suggesting that accumulation of advanced glycation end products is implicated in renal extracellular matrix accumulation in diabetes and that early intervention in this process can ameliorate long-term functional and structural features of diabetic nephropathy. The ability of ALT-711 to modulate renal AGE accumulation as well as associated molecular and cellular processes implicated in diabetic nephropathy such as prosclerotic cytokines and extracellular matrix accumulation provides the potential for a new treatment for progressive diabetic renal disease. It is now worth considering, particularly in the context of human diabetes, whether ALT-711 or related compounds may confer significant renoprotection.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1102fje; doi: 10.1096/fj.02-1102fje 
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P< 0.01 DALT early vs. DALT late, #P< 0.05 vs. diabetic.
