Prevention of early renal disease, dyslipidaemia and lipid peroxidation in STZ-diabetic rats by LR-9 and LR-74, novel AGE inhibitors

Figarola, James L.; Scott, S. D.; Loera, Sofia; Xi, Bixin; Synold, Timothy W.; Weiss, Lawrence M.; Rahbar, Samuel

doi:10.1002/dmrr.550

Cited by 20 publications

(13 citation statements)

References 62 publications

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“…At the age of 13 weeks, the animals were divided into the following groups: (1) ZL rats (n=6); (2) ZDF rats without treatment (n=6); and (3) ZDF rats treated with LR-90 at 50 mg/l in their drinking water (ZDF90, n=6). The dose of LR-90 was chosen after previous experiments with type 1 diabetic nephropathy [25]. Food, water intake, body weight and blood glucose levels were monitored periodically.…”

Section: Methodsmentioning

confidence: 99%

“…More recently, several of these compounds were found effective in preventing the development of diabetic nephropathy in streptozotocin-induced diabetic animals [24,25]. In the present study, we evaluated whether LR-90, one of the more powerful AGE inhibitors with other biochemical effects (lipid-lowering, antioxidant, anti-inflammatory) [22,23,26], can prevent dyslipidaemia and the development of renal dysfunction in experimental models of type 2 diabetes.…”

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confidence: 99%

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

et al. 2008

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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.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2008

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“…Several publications report on the simultaneous presence of both CML and the lipid peroxidation adducts 4-hydroxynonenal (HNE) and malondialdehyde (MDA) at sites of inflammation [7,8]. Furthermore, Figarola et al [9] reported that streptozotocin (STZ)-induced diabetic rats treated with either of two anti-AGE/ALE drugs (LR-7, LR-74) showed reduced albuminuria, hyperlipidemia, lipid peroxidation and CML levels but this was not associated with an effect on hyperglycemia measured as plasma glucose and HbA1 C . These results suggest that these drugs can reduce lipid per-oxidation, resulting in the reduction of CML levels but not in the reduction of hyperglycemia or the glycation product of hemoglobin.…”

Section: Introductionmentioning

confidence: 98%

N^ε‐carboxymethyllysine‐modified proteins are unable to bind to RAGE and activate an inflammatory response

Buetler¹,

Leclerc

Baumeyer

et al. 2008

Molecular Nutrition Food Res

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Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are generally thought to be ligands of the receptor for AGEs, RAGEs. It has been argued that this results in the activation of pro-inflammatory pathways and diseases. However, it has not been shown conclusively that a CML-modified protein can interact directly with RAGE. Here, we have analyzed whether beta-lactoglobulin (bLG) or human serum albumin (HSA) modified chemically to contain only CML (10-40% lysine modification) can (i) interact with RAGE in vitro and (ii) interact with and activate RAGE in lung epithelial cells. Our results show that CML-modified bLG or HSA are unable to bind to RAGE in a cell-free assay system (Biacore). Furthermore, they are unable to activate pro-inflammatory signaling in the cellular system. Thus, CML probably does not form the necessary structure(s) to interact with RAGE and activate an inflammatory signaling cascade in RAGE-expressing cells.

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“…11) Synthetic products such as aminoguanidine, 12) LR compounds [13][14][15] and naturally occurring compounds such as flavonoids, 16) cinnamon bark proanthocyanidins 17) have been studied for their antiglycation activities in vitro and in vivo. The flower of the safflower plant, Carthamus tinctorius L., has been broadly used in traditional Chinese medicine for treatment of cerebrovascular and cardiovascular diseases.…”

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confidence: 99%

Inhibitory Effects of Hydroxysafflor Yellow A on the Formation of Advanced Glycation End Products <i>in Vitro</i>

Zhuge

et al. 2012

Biological & Pharmaceutical Bulletin

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To investigate the inhibitory effects of hydroxysafflor yellow A (HSYA) on the protein glycation in vitro. Using bovine serum albumin (BSA)-glucose assay, BSA-methylglyoxal (MGO) assay, and N-acetylglycyl-lysine methyl ester (G.K.) peptide-ribose assay, inhibitory effects of HSYA were investigated. Advanced glycation end products (AGEs) production was assessed by AGEs-specific fluorescence and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In BSA-glucose assay, HSYA concentration dependently decreased AGEs formation, with maximum inhibitory effects at 1 mM by 95%. Further more, HSYA also showed significant inhibitory effects on MGO-medicated protein modification and subsequent cross-linking of proteins. Finally, when co-incubated with G.K. peptide and ribose, HSYA exhibited its antiglycation effects, and the maximum inhibitory effects of HSYA at 1 mM were 84%. Overall, our present study provides the first evidence of the antiglycation effects of HSYA on AGEs formation in vitro.

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Prevention of early renal disease, dyslipidaemia and lipid peroxidation in STZ-diabetic rats by LR-9 and LR-74, novel AGE inhibitors

Cited by 20 publications

References 62 publications

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

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

N^ε‐carboxymethyllysine‐modified proteins are unable to bind to RAGE and activate an inflammatory response

Inhibitory Effects of Hydroxysafflor Yellow A on the Formation of Advanced Glycation End Products <i>in Vitro</i>

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Prevention of early renal disease, dyslipidaemia and lipid peroxidation in STZ-diabetic rats by LR-9 and LR-74, novel AGE inhibitors

Cited by 20 publications

References 62 publications

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

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

Nε‐carboxymethyllysine‐modified proteins are unable to bind to RAGE and activate an inflammatory response

Inhibitory Effects of Hydroxysafflor Yellow A on the Formation of Advanced Glycation End Products <i>in Vitro</i>

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N^ε‐carboxymethyllysine‐modified proteins are unable to bind to RAGE and activate an inflammatory response