Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition.

Gilbert, Richard E.; Cox, Allison; Wu, Linlin; Allen, Terri J.; Hulthén, U L; Jerums, George; Cooper, Mark E.

doi:10.2337/diabetes.47.3.414

Cited by 204 publications

(162 citation statements)

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“…In support of this, Ang II has been shown to induce marked glomerular sclerosis 27 with cell proliferation of the glomerular mesangium, 28 vascular endothelium, 29 tubular epithelium 30 and the vascular smooth muscle. 31 Ang II causes podocyte injury by increasing glomerular capillary pressure through a selective constriction of efferent arterioles.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

et al. 2009

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Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg À1 per day, p.o.) or ARB (olmesartan, 5 mg kg À1 per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-b mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

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Section: Discussionmentioning

confidence: 99%

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

et al. 2009

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“…40,52 Studies in animal models of diabetes or hypertension suggest that the therapeutic benefits of ARBs and ACE inhibitors might be mediated through a number of mechanisms, including suppression of MCP-1, 28 inhibition of collagen synthesis and stimulation of metalloproteinase activity, 27 prevention of loss of glomerular nephrin, 53 and prevention of overexpression of TGF-b1 and type IV collagen. 54 Evidence also suggests that improved glomerular permselectivity may contribute to renoprotection. 55 …”

Section: Pathophysiologymentioning

confidence: 99%

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

Karalliedde

Viberti

2006

J Hum Hypertens

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The incidence of end-stage renal disease (ESRD) is rising worldwide, accompanied by corresponding increases in the risk of morbidity and mortality. Underlying this trend are increasing rates of hypertension and diabetes mellitus, the two most common causes of ESRD. In addition to the adverse haemodynamic effects of hypertension on the kidney, elevated blood pressure (BP) can activate components of the renin-angiotensinaldosterone system (RAAS), which, in turn, activate mediators of inflammation, oxidative stress, cell growth, and matrix accumulation. Lowering BP reduces the risk of cardiovascular events and renal damage. Accumulating evidence from clinical and laboratory studies suggests that interrupting the RAAS with therapies such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone receptor blockers can interfere with the mechanisms that promote diabetic and non-diabetic renal damage. Moreover, clinical trials of RAAS blockade have demonstrated reductions in microalbuminuria, a predictor of increased cardiorenal risk and overt nephropathy in patients with and without diabetes and/or hypertension. In this way, agents that block the RAAS should be considered the drugs of first choice as they provide enhanced renoprotection compared with other classes of antihypertensive agents such as calcium channel blockers and b-blockers.

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“…Rats from group 5 received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 of the AT1-receptor antagonist losartan in their drinking water. The selected doses of ramipril (1 mg⅐kg Ϫ1 ⅐day Ϫ1 ) and losartan (10 mg⅐kg Ϫ1 ⅐day Ϫ1 ) have been previously demonstrated to reverse many functional and morphological events of DN (24,55). For its part, the dose of HOE-40 (0.25 mg/kg) is twofold that of a dose demonstrated to inhibit the hypotensive effects of BK in vivo (40).…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B2 kinin receptor (B2R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B2R activation. These observations are consistent with a potential therapeutic role of BK and B2R during glomerulosclerosis.

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Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition.

Cited by 204 publications

References 0 publications

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

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