Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat

Davis, Bonnie M.; Forbes, Josephine M.; Thomas, Merlin C.; Jerums, George; Burns, Wendy C.; Kawachi, Hiroshi; Allen, Terri J.; Cooper, Mark E.

doi:10.1007/s00125-003-1256-8

Cited by 61 publications

(49 citation statements)

References 57 publications

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We agree with R. Biswas et al that our recent study did not find the combination of aminoguanidine and perindopril to afford total renoprotection or to be superior to monotherapy in terms of all renal parameters studied [1]. We consider albuminuria to be a major functional marker of diabetic nephropathy, and demonstrated in our recent study that the combination was superior to individual agents in attenuating the progressive increase in albumin excretion rate in diabetic spontaneously hypertensive rats [1].

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confidence: 84%

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2004

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We agree with R. Biswas et al. that our recent study did not find the combination of aminoguanidine and perindopril to afford total renoprotection or to be superior to monotherapy in terms of all renal parameters studied [1]. We consider albuminuria to be a major functional marker of diabetic nephropathy, and demonstrated in our recent study that the combination was superior to individual agents in attenuating the progressive increase in albumin excretion rate in diabetic spontaneously hypertensive rats [1]. However, other markers of renal injury such as renal TGFβ expression and glomerular and tubulointerstitial injury, although reduced by both forms of monotherapy, were not further decreased by combination therapy.We agree that perindopril and indeed other agents that interrupt the renin-angiotensin system, such as AII antagonist, are inhibitors of AGE formation, as initially reported in in vitro studies [2]. Indeed, our group has reported in vivo AGE inhibition with the ACE inhibitor, ramipril [3] and more recently in diabetic spontaneously hypertensive rats with perindopril [1]. This in vivo inhibition has now been confirmed in another model of diabetic nephropathy using the AII antagonist, irbesartan [4]. Interestingly, hydralazine was also reported to decrease AGE formation [4], and previous studies suggest that dihydropyridine calcium channel blockers do not inhibit AGE formation [2].Our own group has, over the last 10 to 15 years, investigated a number of antihypertensive agents in diabetic spontaneously hypertensive rats, and demonstrated antiproteinuric effects with the combination of hydralazine and metoprolol [5] but not with the calcium channel blockers, amlodipine [6] or lacidipine [7]. Although, at the time, we did not appreciate that some of these antihypertensive agents were AGE inhibitors, it is interesting to speculate that one of the potential explanations for the renoprotection that is conferred by some but not other antihypertensive agents may in fact be related to the specific drug's ability to modulate the glycation pathway.We acknowledge that one must be cautious in interpreting the findings of rodent studies when placed in a human context. Indeed, the dose of agents such as ACE inhibitors is likely to be an important factor in determining the degree of renoprotection. However, in this study [1], we wanted to compare equivalent doses of ACE inhibition, with or without additional inhibition of AGE formation with aminoguanidine, and were able to show that for the same blood pressure reduction, the combination was more potent at reducing albumin excretion rate. However, as alluded to by Biswas et al., no such reduction in the relatively mild renal structural abnormalities could be demonstrated.

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confidence: 84%

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2004

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“…To develop innovative therapeutic alternatives for combating diabetic nephropathy, a comprehensive understanding of the pathophysiology of this disease is imperative. In addition, targeting multiple risk factors associated with the prevention and progression of type 2 diabetic nephropathy seems more likely to be beneficial, as shown by recent approaches [33,34]. Our current studies demonstrate the possibility of preventing diabetic nephropathy in a rat model of type 2 diabetes using LR-90, a compound that was initially identified as an AGE inhibitor and has recently been shown to exhibit other properties such as metal chelator, antioxidant, free radical scavenger and anti-inflammatory compound [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

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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“…It was hoped that by excluding hypertension, which is a known independent contributor to renal fibrosis and is associated with renal AGE accumulation [37], we would be able to examine the independent effect of AGE accumulation on secondary renal injury. Certainly, hypertension and AGE accumulation appear to have synergistic effects, as demonstrated by accelerated nephropathy in spontaneously hypertensive rats with diabetes, in which a combination of blood pressure reduction and inhibition of AGE formation have greater benefit than either therapy alone [37].…”

Section: Discussionmentioning

confidence: 99%