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

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.

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

“…6). Diabetic glomerulosclerosis is characteristics of late diabetes and usually found in renal tissue of long-term diabetic rats and TGF-β1 was a key mediator of diabetic glomerulosclerosis [12][13][14]. In contrast, in our study, diabetic rats were induced only for 8 and 16 weeks, thereby no diabetic glomerulosclerosis was observed and intensive insulin treatment may be induced too early to observe the difference in the early and late treatment groups.…”

“…We last tested the expression of TGF-β1, which could stimulate p38 MAPK expression [12][13]. The mRNA levels of renal cortical TGF-β1 in the 8wDM and 16wDM groups were 1.50 ± 0.47 and 1.81 ± 0.83 fold higher respectively, in comparison to the 16wNC group (p<0.05).…”

A New Perspective on Therapeutic Inhibition of Advanced Glycation in Diabetic Microvascular Complications: Common Downstream Endpoints Achieved Through Disparate Therapeutic Approaches?

“…This is most clearly demonstrated by the renoprotection which is seemingly afforded with HMG CoA reductase inhibitors [102,103,104]. Interestingly, the majority of the AGE inhibitors assessed in this review (table 1) have been reported to improve lipid profiles in diabetic patients [99], as well as in experimental models of diabetic complications [31, 33, 64, 67, 69, 79, 105, 106]. Effects of RAS blockers, sRAGE and TZDs in plasma lipids have not been previously reported.…”

“…It is thought to reduce AGE accumulation via its potent metal chelating abilities and its interaction with reactive carbonyl species [65]. Moreover, its renoprotective benefits, such as improvements in albuminuria, creatinine clearance and glomerular sclerotic index, have been demonstrated in experimental models of both type 1 and type 2 diabetic nephropathy [64, 65]. …”

“…LR-90 (methylene bis-[4,4′-(2-chloropheylureido phenoxysiobutyric acid)]) has been identified as a potent inhibitor of renal and circulating AGE accumulation [64, 65]. It is thought to reduce AGE accumulation via its potent metal chelating abilities and its interaction with reactive carbonyl species [65].…”