The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

Xu, Jian; Meng, Kexin; Zhang, Rui; He, Yang; Liao, Chia-Shu; Zhu, Wenliang; Jiao, Jundong

doi:10.1371/journal.pone.0097906

Cited by 4 publications

(4 citation statements)

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“…Inhibition of HO-1 by the antagonist, ZnPP, increased autophagy in the mesangial cells stimulated with H 2 O 2 . A previous study demonstrated that activation or inactivation of HO-1 does not alter basal autophagy (21). The results of the present study indicated that the effect of HO-1 on reducing autophagy may be ROS-dependent in glomerular mesangial cell.…”

Section: Activation Of Ho-1 Reverses H 2 O 2 -Induced Autophagysupporting

confidence: 51%

“…The HO-1-induced effect was also demonstrated to be dose-dependant, as HO-1 successfully inhibited the increasing autophagy caused by H 2 O 2 . However, no significant alteration in the basal autophagy level was detected in normal mesangial cells through the pharmacological intervention of HO-1 activity (21). This implies that the HO-1-mediated control of autophagy may be ROS-dependent.…”

Section: Discussionmentioning

confidence: 88%

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Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Wang

et al. 2016

Molecular Medicine Reports

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Abstract.Increasing evidence has demonstrated that the activation of heme oxygenase (HO)-1 reduces autophagy stimulated by oxidative stress injury, in which the supraphysiological production of reactive oxygen species (ROS) is detected. However, the potential mechanism underlying this effect remains unclear. The present study aimed to investigate the function of HO-1 activation in the regulation of autophagy in glomerular mesangial cells subjected to H 2 O 2 -induced oxidative stress injury. The results demonstrated that the HO-1 agonist, hemin, reduces the LC3 protein level, which was enhanced by H 2 O 2 treatment. Furthermore, hemin-activated HO-1 may function as a regulator of oxidative stress-induced autophagy in a dose-dependent manner. Pharmacological activation of c-Jun N-terminal kinase (JNK) inhibited the effect of hemin, indicating that the JNK signaling pathway is associated with the mechanism of HO-1 in impeding excessive autophagy. In addition to successfully alleviating H 2 O 2 -induced oxidative stress and cellular apoptosis, hemin-activated HO-1 may provide cytoprotection against rapamycin, a specific autophagy agonist. The present result suggested the inhibitory action of HO-1 in the avoidance of a potentially enhanced linkage between autophagy and apoptosis, particularly in the setting of excessive ROS. Therefore, enhancing the intracellular activity of HO-1 may assist the crosstalk between oxidative stress, autophagy and apoptosis, and represent a novel therapeutic strategy for renal ischemic disease. IntroductionPrevious investigation has demonstrated that heme oxygenase (HO), particularly the stress-responsive isoenzyme HO-1, exhibits vital regulatory functions in renal processes under pathophysiological conditions (1). Due to its beneficial effects, including oxidative stress relief and the inhibition of cell apoptosis, HO-1 has previously been proposed as a potential therapeutic target for ischemia/reperfusion or hypertension-induced glomerular injuries (2,3), and diabetic retinopathy (4). HO-1 has also been considered a potential biomarker of acute kidney injury (5). Multiple mechanisms may be involved in the protective effects of activated HO-1 (6). In a previous study, the effect of HO-1 in autophagy, an apoptosis-associated biological process, was also investigated, and an implication of the comprehensive understanding of the protective mechanisms of HO-1 was provided (7).Autophagy has been widely studied in the last decade (8). The mechanism of autophagy has been elucidated based on pathophysiology to understand human biology and disease (9-11). Autophagy must be reconsidered not only as a self-degrading strategy for cell survival, but also as a type of dynamic and systematic re-organization of cellular materials and energy (12). As such, an appropriate intervention strategy effecting autophagy may direct cellular materials and energy flow to intended processes in order to result in the alleviation of diseases. Therefore, targeting autophagy may be a non-limiting therapeutic strategy ...

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Section: Activation Of Ho-1 Reverses H 2 O 2 -Induced Autophagysupporting

confidence: 51%

Section: Discussionmentioning

confidence: 88%

Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Wang

et al. 2016

Molecular Medicine Reports

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“…Hemin induction of HO-1, in the current study, significantly affected oxidative stress conferred by DN, by reversing all oxidative stress markers tested to more favorable antioxidant status. The nephro-protective effect conveyed by induction of HO-1 was linked to its antioxidant effect in previous studies performed in vitro using H 2 O 2 -treated glomerular mesangial cells [43] and in vivo using other animal models, as polymyxin B-induced nephrotoxicity [44] and gentamicin-induced nephrotoxicity [45]. Here, we also showed that HO-1 induction via HM caused significant reversal of increased renal tissue NO levels, which is in line with previous studies linking the induction of renal HO-1 with that of inducible nitric oxide synthase (iNOS) [33].…”

Section: Discussionmentioning

confidence: 93%

Modulation of heme oxygenase‐1 expression and activity affects streptozotocin‐induced diabetic nephropathy in rats

Ali

Heeba

El-Sheikh

2017

Fundamemntal Clinical Pharma

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Heme oxygenase (HO)-1 has exhibited nephro-protective actions in different animal models; however, its full mechanistic potential in diabetic nephropathy (DN) has not yet been elucidated. Hence, the present study has been undertaken by inducing DN in rats using streptozotocin (50 mg/kg i.p.), with or without either HO-1 inducer; hemin (HM; 40 μmol/kg, s.c.), or HO-1 blocker; zinc protoporphyrin-IX (ZnPP; 50 μmol/kg, i.p.), for one month. Compared to control, rats with DN suffered from hyperglycemia and hyperlipidemia, with signs of renal damage, as assessed by distortion in renal histopathologic architecture and kidney function. Renal oxidative/nitrosative stress was evident by increased malondialdehyde, nitric oxide, myeloperoxidase, with decreased reduced glutathione, superoxide dismutase, and catalase. DN group also exhibited high renal expression of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α, and the apoptotic marker; caspase 3, assessed by Western blot. Renal HO-1 protein expression and activity were increased in DN rats compared to control. Administration of HM, but not ZnPP, to DN rats improved kidney function, histopathologic features, lipid profile, TNF-α, and caspase 3 expressions, with no effect on blood glucose level. HM increased, while ZnPP decreased renal HO-1 activity in DN rats. It is noteworthy that neither intervention affected HO-1 activity or renal oxidative capacity in non-diabetic rats. Interestingly, the expression of HO-1 was upregulated by both HM and ZnPP in DN rats. In conclusion, activation of HO-1 via HM ameliorated renal damage in STZ-induced DN in rats, probably through antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.

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“…It was not surprising that miR-133a, a validated biomarker for osteoporosis ( Wang et al, 2012 ; Li et al, 2014 ), targeted genes in six osteoporosis-related pathways. Based on our previous studies of multi-pathway renoprotectants ( Xu et al, 2014 ), enriched regulation of multiple pathways associated with osteoporosis may suggest a potential functional role for miR-194-5p in the pathogenesis of osteoporosis.…”

Section: Discussionmentioning

confidence: 97%

Identification of miR-194-5p as a potential biomarker for postmenopausal osteoporosis

Meng

Zhang

Pan

et al. 2015

PeerJ

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The incidence of osteoporosis is high in postmenopausal women due to altered estrogen levels and continuous calcium loss that occurs with aging. Recent studies have shown that microRNAs (miRNAs) are involved in the development of osteoporosis. These miRNAs may be used as potential biomarkers to identify women at a high risk for developing the disease. In this study, whole blood samples were collected from 48 postmenopausal Chinese women with osteopenia or osteoporosis and pooled into six groups according to individual T-scores. A miRNA microarray analysis was performed on pooled blood samples to identify potential miRNA biomarkers for postmenopausal osteoporosis. Five miRNAs (miR-130b-3p, -151a-3p, -151b, -194-5p, and -590-5p) were identified in the microarray analysis. These dysregulated miRNAs were subjected to a pathway analysis investigating whether they were involved in regulating osteoporosis-related pathways. Among them, only miR-194-5p was enriched in multiple osteoporosis-related pathways. Enhanced miR-194-5p expression in women with osteoporosis was confirmed by quantitative reverse transcription–polymerase chain reaction analysis. For external validation, a significant correlation between the expression of miR-194-5p and T-scores was found in an independent patient collection comprised of 24 postmenopausal women with normal bone mineral density, 30 postmenopausal women with osteopenia, and 32 postmenopausal women with osteoporosis (p < 0.05). Taken together, the present findings suggest that miR-194-5p may be a viable miRNA biomarker for postmenopausal osteoporosis.

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The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

Cited by 4 publications

References 50 publications

Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Modulation of heme oxygenase‐1 expression and activity affects streptozotocin‐induced diabetic nephropathy in rats

Identification of miR-194-5p as a potential biomarker for postmenopausal osteoporosis

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