Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase‐2 activity and expression in a model of renovascular hypertension

Ceron, Carla S.; Castro, Michele M.; Rizzi, Élen; Montenegro, Marcelo F.; Fontana, Vanessa; Salgado, Maria Cristina O.; Gerlach, Raquel Fernanda; Tanus‐Santos, Jose E.

doi:10.1111/j.1476-5381.2010.00678.x

Cited by 92 publications

(75 citation statements)

References 55 publications

(77 reference statements)

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“…Other antihypertensive drugs were also experimentally shown to down-regulate MMP-2 [35], and therefore, it is possible that antihypertensive drugs used to treat hypertensive disorders of pregnancy ameliorate clinical symptoms by decreasing circulating MMP-2. This suggestion is in line with our results showing that non-responsive GH and PE patients have higher plasma MMP-2 levels, possibly reflecting a worse prognosis for such patients compared with those that responded to therapy.…”

Section: Discussionmentioning

confidence: 99%

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Palei

Sandrim

Amaral

et al. 2012

Basic Clin Pharma Tox

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Imbalanced matrix metalloproteinase (MMP) expression, including MMP-2, has been demonstrated in pre-eclampsia. However, little is known about the effect of polymorphisms in MMP-2 gene on hypertensive disorders of pregnancy. We examined whether two functional MMP-2 polymorphisms (g.-1306C>T and g.-735C>T) are associated with pre-eclampsia and/or gestational hypertension and whether these polymorphisms affect therapeutic responses in women with these conditions. We studied 216 healthy pregnant women (HP), 185 patients with gestational hypertension (GH) and 216 patients with pre-eclampsia (PE). They were stratified as responsive or non-responsive to antihypertensive therapy according to clinical and laboratorial parameters of therapeutic responsiveness. Genomic DNA was extracted from whole blood and genotypes for g-1306C>T and g.-735C>T polymorphisms were determined by real-time PCR using Taqman allele discrimination assays. Haplotype frequencies were inferred using the PHASE 2.1 program. The distributions of MMP-2 genotypes and haplotypes were similar in HP, GH and PE patients (p > 0.05). In addition, we found no significant differences in MMP-2 genotype or haplotype frequencies when GH or PE patients were classified as responsive or non-responsive to antihypertensive therapy (p > 0.05). Our results suggest that MMP-2 polymorphisms do not affect the susceptibility to hypertensive disorders of pregnancy. In parallel, MMP-2 polymorphisms apparently do not affect the responsiveness to antihypertensive therapy of women with these hypertensive disorders of pregnancy.Pre-eclampsia is a fairly common clinical condition characterized by new-onset hypertension and proteinuria during pregnancy, probably as a result of inadequate trophoblast invasion of the maternal uterine spiral arteries and poor placental perfusion [1]. Reduced blood flow promotes placental release of vasopressors [2], oxidative stress and pro-inflammatory alterations leading to vascular dysfunction [3].Matrix metalloproteinases (MMPs) are a family of structurally related, zinc-dependent enzymes with multiple functions and tissue distribution. Their activity target extracellular matrix components during development and morphogenesis [4]. Specifically, MMP-2 is involved in remodelling of placental and uterine arteries [5,6], and abnormal MMP-2 expression has been reported in hypertensive disorders of pregnancy [7][8][9][10].Under normal circumstances, MMP-2 activity is regulated at the level of transcription, activation of latent forms and inhibition by endogenous MMP inhibitors (tissue inhibitors of metalloproteinase; TIMPs) [4]. In this respect, two functional MMP-2 genetic polymorphisms apparently affect MMP-2 transcriptional levels: the g.-1306C>T and the g.-735C>T. In vitro studies showed that the 'C' to 'T' substitutions at 1306 and 735 positions in promoter region of MMP-2 gene, respectively, result in increased MMP-2 transcription [11,12]. Interestingly, while both polymorphisms have been associated with hypertension-related complications...

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Section: Discussionmentioning

confidence: 99%

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Palei

Sandrim

Amaral

et al. 2012

Basic Clin Pharma Tox

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“…Second, we studied a relatively small number of patients, and this may have limited our chances to detect differences between the groups. Third, the patients included in the present study were under pharmacological treatment, and this may have altered MMP-2 and/or TIMP-2 levels [29,30]. However, it is clearly unacceptable not to treat uremic patients.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Marson¹,

Lacchini²,

Belo³

et al. 2012

Am J Nephrol

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Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C^–1306T and C^–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C^–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C^–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants.

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“…In addition, it is well known that ROS affects the entire RAS signaling in bone marrow (BM) cells (Ruiz-Ortega et al, 2001;Ceron et al, 2010), which are known to participate in tissue repair (Cuende et al, 2012).…”

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confidence: 99%

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

Campagnaro

Tonini

Doche

et al. 2013

DNA and Cell Biology

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Angiotensin II (Ang II), which plays a pivotal role in the pathophysiology of the two-kidney, one-clip (2K1C) Goldblatt hypertension, has been associated with augmented generation of reactive oxygen species (ROS) in some cells and tissues. In the present study, we evaluated the influence of 2K1C hypertension on oxidative stress, DNA fragmentation, and apoptosis of bone marrow (BM) cells. Two weeks after the renal artery clipping or Sham operation, flow cytometry analysis showed a higher production of superoxide anions (approximately sixfold) and hydrogen peroxide (approximately twofold) in 2K1C hypertensive than in Sham normotensive mice. 2K1C mice also showed an augmented DNA fragmentation (54%) and apoptotic cells (21%). Our data show that the 2K1C renovascular hypertension is characterized by an increased production of ROS, DNA damage, and apoptosis of BM, which is a fundamental source of the cells involved in tissue repair.

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Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase‐2 activity and expression in a model of renovascular hypertension

Abstract: SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension-induced MMP-2 up-regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension.

Cited by 92 publications

References 55 publications

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

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