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Diabetologia
Published in: Diabetologia 5/2008

01-05-2008 | Article

LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat

Authors: J. L. Figarola, S. Loera, Y. Weng, N. Shanmugam, R. Natarajan, S. Rahbar

Published in: Diabetologia | Issue 5/2008

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Abstract

Aims/hypothesis

Previous studies have shown that LR-90, a new inhibitor of AGE formation, prevented the development of experimental type 1 diabetic nephropathy. In this study, we examined the effects of LR-90 in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes and metabolic syndrome, and investigated the mechanisms by which it may protect against renal injury.

Methods

Male ZDF rats were treated without or with LR-90 from age 13 to 40 weeks. Metabolic and kidney functions and renal histology were evaluated. AGE accumulation and the production of the receptor for AGE (AGER) were measured. Profibrotic growth factors, extracellular matrix proteins and intracellular signalling pathways associated with glomerular and tubular damage were also analysed.

Results

LR-90 dramatically reduced plasma lipids in ZDF rats, with only modest effects on hyperglycaemia. Renal AGE, AGER and lipid peroxidation were all attenuated by LR-90. LR-90 significantly retarded the increase in albuminuria and proteinuria. This was associated with reduction in glomerulosclerosis and tubulointerstitial fibrosis, concomitant with marked inhibition of renal overproduction of TGF-β1, connective tissue growth factor, fibronectin and collagen IV. Additionally, LR-90 downregulated the activation of key mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) in the renal cortex.

Conclusions/interpretation

These results support our earlier studies on the renoprotective effects of LR-90 on type 1 diabetic nephropathy and provide further evidence that LR-90, an AGE inhibitor with pleiotrophic effects, may also be beneficial for the prevention of type 2 diabetic nephropathy, where multiple risk factors, such as hyperglycaemia, dyslipidaemia, obesity, insulin resistance and hypertension, contribute to renal injury.
Appendix
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Metadata
Title
LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat
Authors
J. L. Figarola
S. Loera
Y. Weng
N. Shanmugam
R. Natarajan
S. Rahbar
Publication date
01-05-2008
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-008-0935-x

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