title: LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat.
abstract: OBJECTIVE
  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-beta1, 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-kappaB) in the renal cortex.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Diabetes, Endocrinology and Metabolism, Gonda Building, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Figarola
authors.forename: S
authors.initials: S
authors.lastname: Loera
authors.forename: Y
authors.initials: Y
authors.lastname: Weng
authors.forename: N
authors.initials: N
authors.lastname: Shanmugam
authors.forename: R
authors.initials: R
authors.lastname: Natarajan
authors.forename: S
authors.initials: S
authors.lastname: Rahbar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure; D002087:Butyrates / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D050171:Dyslipidemias / Q000517:prevention & control*; D006339:Heart Rate; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002087:Butyrates; C485003:LR-90; D014280:Triglycerides