Involvement of angiotensin II and endothelin in matrix protein production and renal sclerosis

Ruíz-Ortega, Marta; Gómez‐Garre, Dulcenombre; Alcázar, Roberto; Palacios, Itziar; Bustos, C.; Gonzalez, Sara Sierra; Plaza, Juan José González; González, Eva; Egido, J.

doi:10.1097/00004872-199407030-00008

Cited by 58 publications

(44 citation statements)

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“…A study in this model of Superior renoprotective effects of combination therapy with ACE and AGE inhibition 93 hypertension and diabetes has shown that, despite an equihypotensive effect of the angiotensin II receptor blocker, valsartan and the dihydropyridine calcium channel blocker, amlodipine, renoprotection as assessed by reductions in albuminuria and glomerulosclerosis was afforded by valsartan only [33]. As angiotensin II (AII), the effector peptide of the RAS, has been shown to have growth-like properties [34,35] the beneficial effects observed with perindopril, and thus the progression of albuminuria in this model, may only partly be explained by effects on systemic blood pressure. Angiotensin II has been implicated in the stimulation of transforming growth factor β1 (TGFβ1), a prosclerotic cytokine considered pivotal in the progression of diabetic renal complications [8,36].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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Aims/hypothesis. Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension. Method. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks. Results. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFβ1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine. Conclusion/interpretation. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury. [Diabetologia (2004) Based on clinical and experimental studies, the two main risk factors linked to the pathogenesis of diabetic vascular complications are hyperglycaemia and systemic hypertension [1,2,3,4]. However, the interaction between these two pathways and their involvement in the pathogenesis of diabetic renal microvascular complications is not clear. Studies by our own group and others, in both the experimental and clinical setting have shown the renoprotective effects of antihypertensive agents that block the renin-angiotensin system (RAS) [1,5,6,7]. The renal effects of these agents include reduced development of albuminuria and less glomerular and tubulointerstitial injury [8]. The effects of ACE inhibitors on renal structural injury have been mediated via the prosclerotic cytokine,

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Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…28 The inhibitory effect of ET A receptor blockade on the development of glomerulosclerosis and of interstitial or vascular lesions appears plausible in view of the known renal actions of ET-1, ie, mitogenic effects on mesangial cells 29,30 and increased expression of fibronectin and collagen. 7,31 Furthermore, ET-1 stimulates the production of cytokines such as platelet-derived growth factor. 30 In the rat kidney, ET A receptors have been demonstrated in mesangial cells and ET B receptors in endothelial and epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Nephroprotection of an ET _A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

et al. 1998

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Abstract-The present study was designed to assess whether the orally active and highly specific endothelin A (ET A ) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET A receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.(Hypertension. 1998;31:995-1001.)

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“…56 In addition, Ang II causes mesangial cell growth and matrix production. 57, 58 The ACEis reduce glomerular capillary pressure by decreasing arterial pressure and selectively dilating efferent arterioles. 59 Numerous animal studies and small clinical trials have suggested that ACEis significantly reduce the loss of kidney function in diabetic nephropathy.…”

Section: Diabetic Nephropathymentioning

confidence: 99%

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

2009

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Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. INTRODUCTIONIn recent years, stressful and fiercely competitive lifestyles and food habits have compounded the problems of hypertension. Long-standing and stressful, progressively rising hypertension can lead to many disorders, including myocardial infarction (MI), cerebrovascular events, congestive heart failure, peripheral arterial insufficiency, premature mortality 1 and renal dysfunction leading to glomerulosclerosis and kidney artery aneurysm. 2 A number of therapies are available, but angiotensin-converting enzyme (ACE) inhibitors have been the preferred first-line therapy for hypertension, congestive heart failure, left ventricular (LV) systolic dysfunction and MI. 3,4 ACE inhibitors (ACEis) have been in use for the past two decades, and the interest in them is still growing. Recently, the discovery of domain-selective ACEis and new members of the renin-angiotensin system (RAS) (that is, angiotensin-converting enzyme 2) have again fueled the interest of researchers. Some new studies have expanded the already impressive clinical profile of ACEis. This review traces some already known and new facets of ACE inhibition and introduces new advances in the designing of a new generation of ACEis.

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Involvement of angiotensin II and endothelin in matrix protein production and renal sclerosis

Cited by 58 publications

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

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

Nephroprotection of an ET _A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

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Involvement of angiotensin II and endothelin in matrix protein production and renal sclerosis

Cited by 58 publications

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

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

Nephroprotection of an ET A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

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Nephroprotection of an ET _A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats