p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 1. p38 MAPK-Dependent Endothelial Dysfunction and Hypertension

Ju, Haisong; Behm, David J.; Nerurkar, Sandyha; Eybye, Marianne; Haimbach, Robin E.; Olzinski, Alan R.; Douglas, Stephen A.; Willette, Robert N.

doi:10.1124/jpet.103.057422

Cited by 58 publications

(54 citation statements)

References 27 publications

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“…Consistent with the histological changes observed in the kidney, albuminuria was significantly reduced in the SFD ϩ SB-239063 group. It is noteworthy, that the beneficial effects of p38 MAPK inhibition may have been underestimated in this study in that 80% of SFD ϩ SB-239063 animals survived the protocol compared with only 50% in the SFD control group (similar results as in Part 1 of this study; Ju et al, 2003). Thus we were unable to assess the severe renal dysfunction that is known to accompany morbidity in the SFD control group.…”

Section: Discussioncontrasting

confidence: 47%

“…Part 1 of this study (Ju et al, 2003) illustrates the role of p38 MAPK in endothelial dysfunction associated with a salt/ fat-sensitive model of hypertension and the reversal of this dysfunction after p38 MAPK inhibition. In Part 2 of this study, we examined the role of p38 MAPK inhibition on the renal dysfunction associated with this salt/fat-sensitive model of hypertension.…”

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confidence: 99%

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p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 2. Improved Renal Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Lenhard

Nerurkar²,

Schaeffer³

et al. 2003

J Pharmacol Exp Ther

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Recent evidence suggests p38 mitogen-activated protein kinase (MAPK) signal transduction plays an important role in the pathogenesis of progressive renal disease. Using dynamic contrast enhanced magnetic resonance imaging (MRI), we evaluated chronic treatment with a p38 MAPK inhibitor, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl-methoxypyridimidin-4-yl)imidazole (SB-239063), on renal function in a hypertension model of progressing renal dysfunction. Spontaneously hypertensive-stroke prone rats were placed on a high salt/fat diet (SFD) or maintained on normal chow diet (ND). SFD animals with albuminuria at 4 to 8 weeks (Ն10 mg/day inclusion criteria), were randomized into p38 MAPK inhibitor treatment (SB-239063, 1200 ppm in diet) or vehicle groups. The progression of blood pressure and albuminuria during the treatment period (ϳ6 weeks) was decreased by 12 and 60%, respectively, in the SFD ϩ SB-239063 versus SFD control group. Renal perfusion and filtration were assessed by in vivo MRI at the end of the study. Relative cortical perfusion was increased in the SFD ϩ SB-239063 group compared with the SFD control group as reflected by a 29% decrease in time to peak of contrast agent in the cortex. Additionally, the regional renal glomerular filtration rate index (K cl ) was increased by 39% in the SFD ϩ SB-239063 versus SFD control group and was normalized to the ND control group. Greater functional heterogeneity was observed in the SFD control versus SFD ϩ SB-239063 or ND control group. All alterations of renal function were supported by histopathological findings. In conclusion, chronic treatment with a p38 MAPK inhibitor, SB-239063, attenuates functional and structural renal degeneration in a hypertensive model of established renal dysfunction.

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Section: Discussioncontrasting

confidence: 47%

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confidence: 99%

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 2. Improved Renal Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Lenhard

Nerurkar²,

Schaeffer³

et al. 2003

J Pharmacol Exp Ther

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“…Many studies have associated increased levels of cytokines or high glucose levels in the bloodstream with increased p38 activity and endothelial dysfunction (1)(2)(3)(4). The mechanism controlling endothelial dysfunction is not clearly understood.…”

Section: Fig 9 Mek6e-induced Migration and Actin Reorganization Invmentioning

confidence: 99%

“…However, several pathological conditions such as hypertension and hyperglycemia are accompanied by a dysfunctional endothelium characterized by impaired re-endothelialization. These conditions are associated with elevated levels of cytokines such as tumor necrosis factor and transforming growth factor-␤ as well as enhanced activation of p38 (1)(2)(3)(4)(5). Interestingly, high glucose levels present in diabetic patients have also been shown to induce the activation of p38 (1).…”

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confidence: 99%

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

McMullen

Bryant

Glembotski

et al. 2005

Journal of Biological Chemistry

136

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Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.

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“…Several mechanisms have been proposed for druginduced prolongation of life span in SHRSP: 1) reduction of BP (20,26,27), 2) modulation of inflammation (26,28), 3) prevention of extracellular matrix accumulation (29), 4), inhibition of superoxide production (28), and 5) reduction of platelet aggregation (27). In this study, we examined the dosing-time-dependent effects of Val on BP and IL-1β and IL-6 levels, the markers of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Chronopharmacology of Angiotensin II–receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats

et al. 2011

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Abstract. Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosingtime-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

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p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 1. p38 MAPK-Dependent Endothelial Dysfunction and Hypertension

Cited by 58 publications

References 27 publications

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 2. Improved Renal Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 2. Improved Renal Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

Chronopharmacology of Angiotensin II–receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats

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