Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse

Wei, Huang; Gallois, Yves; Bouby, Nadine; Bruneval, Patrick; Heudes, Didier; Bélair, Marie‐France; Krege, John H.; Meneton, Pierre; Marre, Michel; Smithies, Oliver; Alhenc-Gélas, François

doi:10.1073/pnas.231476798

Cited by 134 publications

(125 citation statements)

References 33 publications

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“…Until now, only one study has suggested the involvement of BK in the antiproteinuric effect of ACEI in DN (65), whereas absence of B2R is associated with higher microalbuminuria in diabetes mice (34). It has been demonstrated that DN is markedly enhanced in mice expressing high ACE activity, a situation associated with low levels of kinin and thereby low B2R activation (29). Similar observations have been reported in mice lacking the B2R (34).…”

Section: Discussionmentioning

confidence: 61%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

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Section: Discussionmentioning

confidence: 61%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Huang et al (20) induced diabetes in mice that had one, two, or three copies of the ACE gene. Twelve weeks later, the three-copy diabetic mice had increased BP and overt proteinuria.…”

Section: Angii Receptorsmentioning

confidence: 99%

“…Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels leads to aggravation of diabetic nephropathy in mice in comparison with reduced ACE gene expression (20). These data indicate that there likely is some genetic influence on the activity of the RAAS, but how this translates into the individual risk for predisposition or progression of renal disease remains unclear.…”

Section: Angii Receptorsmentioning

confidence: 99%

Renin-Angiotensin-Aldosterone System and Progression of Renal Disease

Rüster

Wolf

2006

Journal of the American Society of Nephrology

402

316

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Inhibition of the renin-angiotensin-aldosterone system (RAAS) is one of the most powerful maneuvers to slow progression of renal disease. Angiotensin II (AngII) has emerged in the past decade as a multifunctional cytokine that exhibits many nonhemodynamic properties, such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. Many of these deleterious functions are mediated by other factors, such as TGF-␤ and chemoattractants that are induced in the kidney by AngII. Moreover, understanding of the RAAS has become much more complex in recent years with the identification of novel peptides (e.g., AngIV) that could bind to specific receptors, elucidating deleterious effects, and non-angiotensin-converting enzyme (ACE)-mediated generation of AngII. The ability of renal cells to produce AngII in a concentration that is much higher than what is found in the systemic circulation and the observation that aldosterone may be engaged directly in profibrogenic processes independent of hypertension have added to the complexity of the RAAS. Even renin has now been identified to have a "life on its own" and mediates profibrotic effects via binding to specific receptors. Finally, drugs that are used to block the RAAS, such as ACE inhibitors or certain AngII type 1 receptor antagonists, may have properties on cells independent of AngII (ACE inhibitor-mediated outside-inside signaling and peroxisome proliferatoractivated receptor-␥ stimulatory effects of certain sartanes). Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of the RAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease.

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“…Huang et al 45 reported glomerular hypertrophy with sporadic interstitial fibrosis and tubular atrophy without any alteration in mesangial morphology and overt glomerulosclerosis in diabetic mice. Examination of kidneys of diabetic nephropathic rats revealed thickening of basement membrane, expansion of mesangial cell and tubular interstitium damage.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Nateglinide and Pioglitazone Combination Therapy Compared With Monotherapy on Diabetic Nephropathy

Bigoniya¹,

Malvi²

2017

Int. J. Res. Ayurveda Pharm.

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The objective of present work is to explore combined effect of nateglinide and pioglitazone on diabetic nephropathy. Nateglinide and pioglitazone were administered to the diabetic nephropathic animals as monotherapy and in median and high dose combination for 28 days. Body weight, relative kidney weight, serum and urine biochemical parameters were analyzed along with kidney tissue antioxidant level and histology. Loss in body weight was efficiently controlled by pioglitazone monotherapy and, nateglinide and pioglitazone high dose combination. Nateglinide treatment significantly (P < 0.05-0.001) reduced serum glucose, blood urea nitrogen (BUN), creatinine and insulin along with decrease in urine albumin and increase in creatinine. Both nateglinide and pioglitazone has significantly (P < 0.05-0.01) reduced glomerular filtration rate (GFR). Nateglinide has nonsignificant effect on kidney antioxidant level but pioglitazone has increased (P < 0.05) superoxide dismutase (SOD) level. Both median and high dose combination significantly (P < 0.05-0.001) reduced the elevated level of serum glucose, cholesterol, triglyceride, low density lipoprotein, BUN, creatinine, insulin and glycated haemoglobin. Combination doses were equally effective in decreasing albumin and increasing creatinine urinary excretion with increase in GFR. High dose combination significantly increased catalase, SOD and glutathione level in the kidney tissue. Monotherapy with nateglinide and pioglitazone reduce hyperglycemia and improve kidney functional ability. Both high and median dose combination of nateglinide and pioglitazone was found effective against disturbed serum and urine biochemical parameters. High dose combination was more effective and beneficial in ameliorating kidney pathological damage and oxidative stress in the treatment of diabetic nephropathy.

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Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse

Cited by 134 publications

References 33 publications

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Renin-Angiotensin-Aldosterone System and Progression of Renal Disease

Efficacy of Nateglinide and Pioglitazone Combination Therapy Compared With Monotherapy on Diabetic Nephropathy

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