Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

Hamano, Yuki; Okude, Takashi; Yokosuka, Osamu; Ogawa, Makoto

doi:10.1159/000331704

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…Telmisartan is an antihypertensive type 1 (AT1) receptor blocker (ARB) for angiotensin II (Ang II). It has pleiotropic anti-inflammatory effects, demonstrates benefits in atherosclerotic lesions in patients and is renoprotective ( Hamano et al, 2011 ; Verdecchia et al, 2011 ). The renin-angiotensin-aldosterone system (RAAS) is knowing to acts in the regulate blood pressure, but authors have also demonstrated that Ang II regulates the expression of NFκB-dependent inflammatory genes ( Jiang et al, 2004 ; Underwood and Adler, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Telmisartan Modulates the Oral Mucositis Induced by 5-Fluorouracil in Hamsters

et al. 2018

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Oral mucositis (OM) is a common adverse effect resulting from cancer therapy. The OM it has implications that may compromise oncologic treatment and decrease the patient’s quality of life. The therapeutic options to prevent or treat the symptoms of OM are scarce; there is no effective therapy that improves the symptoms. Based on the need for further research for the treatment of OM, the present study objective was to evaluate the effect of telmisartan (TELM) on the OM induced by 5-fluorouracil (5-FU), using as animal model Golden Syrian hamsters. 5-FU followed by mechanical trauma on day 4 was used to induce OM in hamsters. Euthanasia occurred on the day 10. The experiments were constituted by the groups saline, mechanical trauma, 5-FU, and TELM in three doses (1, 5, or 10 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The samples also were used for analysis enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reactions (qPCR). TELM (5 or 10 mg/kg) was able to reduce the inflammatory ulceration and infiltration in the oral mucosa of the animals, decreasing the levels of the cytokines TNF-α and IL-1β. These treatments was minimize the immunostaining for cyclooxygenase-2, matrix metalloproteinase-9, transforming growth factor-β, and smad 2/3. The nuclear transcription factor kappa B (NFκB) p65 and inducible nitric oxide synthase were reduced in the oral mucosa. Finally, TELM (10 mg/kg) increased the PPARγ gene expression and reduced STAT1 and NFκB p65 gene expression relative to the 5-FU group. Therefore, TELM prevents the OM produced by 5-FU on animal model.

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Section: Introductionmentioning

confidence: 99%

Telmisartan Modulates the Oral Mucositis Induced by 5-Fluorouracil in Hamsters

et al. 2018

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Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease

Michel

Brunner

Foster

et al. 2016

Pharmacology & Therapeutics

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We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin-angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin-angiotensin system? 2. Are they shared by other inhibitors of the renin-angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.

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Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells

et al. 2013

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Telmisartan, an angiotensin II receptor type 1 blocker (ARB), was recently reported to promote lipolysis in mice by acting as a peroxisome proliferator-activated receptor (PPAR)-δ activator, although in clinical studies, it has also been recognized to activate PPAR-γ as a major cause of its pleiotropic actions. The aim of this study was to investigate whether telmisartan activates endogenous PPAR-δ and thereby exerts anti-fibrotic effects in human mesangial cells (HMC). Immunohistochemical analysis of human renal biopsy specimens revealed that PPAR-δ protein was detected in the HMC of glomeruli with moderately proliferative changes. In the HMC, both GW0742, an authentic PPAR-δ agonist, and telmisartan enhanced PPAR response element (PPRE)-luciferase activity dose dependently, and these increases were blunted by GSK0660, a specific PPAR-δ antagonist, but not by GW9662, a PPAR-γ antagonist. Telmisartan also upregulated the expression of PPAR-δ target genes related to fatty acid oxidation; that is, heart type-fatty acid-binding protein and uncoupling protein-2. These effects were inhibited by both PPAR-δ antagonism and PPAR-δ gene silencing. Transforming growth factor-β1 (TGF-β1) increased the expression of plasminogen activator inhibitor-1 (PAI-1), TGF-β1 and collagen IV. The PAI-1 expression was mediated, at least in part by the phosphorylation of extracellular signal-regulated kinases (ERKs). Telmisartan suppressed TGF-β1-stimulated PAI-1 and collagen IV expression and ERK phosphorylation, and these effects were weakened by PPAR-δ antagonism, whereas eprosartan, a non-PPAR activating ARB, did not affect TGF-β1-stimulated PAI-1 expression. These results indicate that in HMC telmisartan activates endogenous PPAR-δ and may prevent TGF-β1-induced fibrotic changes by reducing ERK phosphorylation in a PPAR-δ-dependent manner, and thus, might be useful for treating hypertensive patients with renal and metabolic disorders.

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Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

Cited by 4 publications

References 23 publications

Telmisartan Modulates the Oral Mucositis Induced by 5-Fluorouracil in Hamsters

Telmisartan Modulates the Oral Mucositis Induced by 5-Fluorouracil in Hamsters

Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease

Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells

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