The vasopeptidase inhibitor AVE7688 ameliorates Type 2 diabetic nephropathy

Schäfer, Stefan; Linz, Wolfgang; Vollert, Henning; Biemer‐Daub, Gabriele; Rütten, Hartmut; Bleich, Markus; Büsch, Andreas

doi:10.1007/s00125-003-1264-8

Cited by 36 publications

(27 citation statements)

References 29 publications

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“…We have previously shown that chronic vasopeptidase inhibition by AVE7688 prevents diabetic nephropathy in ZDF rats [19,22]. The present study demonstrates that AVE7688 also prevents accumulation of the AGEs CML, pentosidine and 3-DG-imidazolone in the diabetic kidney, which offers a mechanistic explanation for the profound nephroprotective effects of vasopeptidase inhibition in the diabetic kidney.…”

Section: Discussionsupporting

confidence: 66%

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Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg −1 ·day −1 ), AVE7688 (45 mg·kg −1 ·day −1 ) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.

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Section: Discussionsupporting

confidence: 66%

“…benzapin-4-carboxy-acid, and its molecular weight is 432.5 g/mol [22]. AVE8048 is the active thiol form of AVE7688.…”

Section: Evaluation Of Chelating Activity Of Ace and Vasopeptidase Inmentioning

confidence: 99%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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“…The nephropathy in this model has been described as focal segmental glomerulosclerosis associated with glomerulomegaly and mesangial expansion [14,15]. Previous studies have shown that the development of diabetic nephropathy in obese ZDF rats can be ameliorated by treatment with peroxisome proliferator-activated receptor-gamma agonists [16,17], ACE inhibitors and angiotensin II receptor blockers (ARBs) [18,19], vasopeptidase inhibitors [19,20], antivascular endothelial growth factor antibodies [21] and antioxidants [15]. These intervention studies strongly suggest that the pathogenesis of renal damage in type 2 diabetes involves a complex interrelationship of metabolic and/or haemodynamic factors.…”

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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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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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“…Accordingly, the aim of our study was to investigate involvement of the RAAS and/or the natriuretic peptide system in the pathophysiology of progressive renal damage after MI. We investigated the renoprotective effects of ACEi with lisinopril versus combined ACE/NEP inhibition with the vasopeptidase inhibitor AVE7688 (21)(22)(23).…”

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confidence: 99%

Renal Damage after Myocardial Infarction Is Prevented by Renin-Angiotensin-Aldosterone-System Intervention

Windt

Eijkelkamp²,

Henning

et al. 2006

Journal of the American Society of Nephrology

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Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosteronesystem and/or vasoactive peptides that are metabolized by neutral endopeptidase (NEP). The renoprotective effect of angiotensin-converting enzyme inhibition (ACEi) as well as combined ACE/NEP inhibition with a vasopeptidase inhibitor (VPI) was investigated in the same model to clarify the underlying mechanism. At week 17 after sequential induction of unilateral nephrectomy and myocardial infarction, treatment with lisinopril (ACEi), AVE7688 (VPI), or vehicle was initiated for 6 wk. Proteinuria and systolic BP (SBP) were evaluated weekly. Renal damage was assessed primarily by proteinuria, interstitial ␣-smooth muscle actin (␣-SMA) staining, and the incidence of focal glomerulosclerosis (FGS). At start of treatment, proteinuria had increased progressively to 167 ؎ 20 mg/d in the entire cohort (n ‫؍‬ 42). Both ACEi and VPI provided a similar reduction in proteinuria, ␣-SMA, and FGS compared with vehicle at week 23 (proteinuria 76 ؎ 6 versus 77 ؎ 4%; ␣-SMA 60 ؎ 6 versus 77 ؎ 3%; FGS 52 ؎ 14 versus 61 ؎ 10%). Similar reductions in systolic BP were observed in both ACEi-and VPI-treated groups (33 ؎ 3 and 37 ؎ 2%, respectively). Compared with ACEi, VPI-treated rats displayed a significantly larger reduction of plasma (41 ؎ 5 versus 61 ؎ 4%) and renal (53 ؎ 6 versus 74 ؎ 4%) ACE activity. It is concluded that both ACEi and VPI intervention prevent renal damage in a rat model of cardiorenal interaction. VPI treatment seemed to provide no additional renoprotection compared with sole ACEi after 6 wk of treatment in this model, despite a more pronounced ACE-inhibiting effect of VPI.

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The vasopeptidase inhibitor AVE7688 ameliorates Type 2 diabetic nephropathy

Cited by 36 publications

References 29 publications

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

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

Renal Damage after Myocardial Infarction Is Prevented by Renin-Angiotensin-Aldosterone-System Intervention

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